The Division of Pediatric Critical Care, University of Florida-Jacksonville.
Tetanus disease has been known to man since the 14th century when John of Arderne, an English surgeon, described a case of tetanus following a gardening injury.(1) While the incidence of tetanus has declined dramatically in the United States, the case fatality rate is still about 20-30% and increases to 50% for those older than 60 years of age.(2,3)
With the successful control of severe reflex muscle spasms by curarization and intermittent positive pressure ventilation the major problem in severe tetanus is the management of circulatory disturbances that occur as a consequence of autonomic dysfunction. Various pharmacological agents have been used to control sympathetic overactivity. Labetalol, a drug with alpha- and beta-adrenergic blocking properties was used in the management of cardiovascular instability in some cases of severe tetanus. In the literature, only one child with severe tetanus received labetalol by continuous infusion to control sympathetic overactivity. Since tetanus is so rare in the United States, many physicians have little experience with its serious complications and management.
We present a case report of a child with severe tetanus, where a labetalol infusion was successfully used in stabilizing the cardiovascular disturbances. We will review the literature, offer a disease overview, present our experience, and discuss tetanus complications with emphasis on the management of autonomic dysfunction in pediatric intensive care unit.
A 12-year old male stepped on a fish bone as he was walking barefoot outside his house. He did not seek medical attention at the time. However, five days later, he developed slight swelling of the left lower leg and started to limp. He had mild back pain and occasional leg spasms. Over the next two days, the patient developed generalized stiffness, back pain, difficulty with swallowing and jaw pain. The patient was taken to a local emergency department where his presumptive diagnosis was tetanus. He received 500 units of tetanus immunoglobulin and was transferred to our institution for admission and treatment.
He had not received any childhood immunizations due to religious beliefs. His past medical history was otherwise noncontributory. On admission his general physical examination was remarkable for swelling and cellulitis of the left foot. His baseline lab values were within acceptable limits except for creatine kinase which was elevated and continued to rise, to a maximum of 1,365 IU on his third day of admission. Epinephrine levels were high in both blood and urine.
After receiving another 2500 units of tetanus antiglobulin, he was taken to the operating room where, during wound debridement, a 6 cm long section of fish bone was removed and bone biopsy showed evidence of necrosis and osteomyelitis. Over the next 24 hours, his condition deteriorated rapidly. He developed tetanic generalized spasms with opisthotonos, risus sardonicus and abdominal rigidity. The patient was transferred to the PICU where he was placed on a continuous infusion of midazolam at 0.1 mg/kg/hr. In addition, he was receiving intermittent boluses of lorazepam, diazepam and morphine sulfate. He continued to have spontaneous spasms every 5 minutes that produced apnea, cyanosis and bradycardia which required mechanical ventilation. While intubated he required an average of 120 mg of midazolam each day by IV constant infusion, as well as diazepam and lorazepam boluses 0.1 mg/kg every 3-4 hours alternatively. He received morphine sulfate up to 60 mcg/kg/hr by infusion. Pancuronium bromide was infused at a rate of 0.1-0.2 mg/kg/hr to control muscle spasms and facilitate mechanical ventilation.
During the second day after intubation, the spasms were controlled but cardiovascular instability continued with sinus tachycardia of 150 beats per minute and intermittent systolic hypertension up to 160 mm Hg. By day 3, there was increasing cardiovascular instability with systolic blood pressure varying from 120-180 mm Hg and heart rate from 80-120 beats per minute. These variations were not always in response to stimulation and occurred despite adequate sedation, analgesia, and use of lidocaine 0.5 mg/kg via endotracheal tube or intravenously before suctioning. Heavy sedation and analgesia failed to provide control of sympathetic overactivity or elevated catecholamine levels in blood and urine.
On day 4, intermittent infusions of labetalol were started. The dose was 0.25 mg/kg, repeated and doubled every 10 minutes as needed, to a maximum of 2 mg/kg/hr. Initially, labetalol boluses produced an immediate fall in systolic blood pressure from 160 to 110 mm Hg and a decrease in the pulse from 125 to 90 beats per minute. This improvement was sustained only for 1 to 2 hours.
The following day, labetalol dosing was switched from intermittent to continuous infusion at 2 mg/hr resulting in sustained control of hypertension. It was possible to reduce sedation and discontinue lorazepam boluses. After 24 hours the labetalol infusion was reduced to 1 mg/hr and systolic blood pressure was maintained in the range of 100-140 mm Hg. Attempts to wean labetalol further were unsuccessful until the sixth day when the labetalol infusion was slowly discontinued.
After one week of intubation, tracheotomy was performed. Interventions were limited to reduce the risk of iatrogenic complications. During the first week of hospitalization, the patient lost 3 kg, despite enteral tube feeding at 1500 kcal/day. It was necessary to increase caloric intake to 2500 kcal/day to maintain positive nitrogen balance and regain weight.
The patient received four weeks of claforan and penicillin. Physical therapy was provided during hospitalization. After three weeks of heavy sedation, neuromuscular paralysis, and mechanical assistance, he was removed from mechanical ventilation. Muscle spasms resolved, however profound weakness continued. He was unable to recall anything of his ICU stay, did not complain of pain, and kept maintained adequate oral nutrition as the enteral diazepam was slowly removed over 7 to 10 days.
Tetanus is an exotoxin-mediated disease. It is caused by Clostridium tetani, an anaerobic, gram positive, spore forming rod. The organism produces two exotoxins; hemolysin, and tetanospasmin, the later is a neurotoxin that is responsible for the clinical manifestation of tetanus disease.(4,5) Tetanospasmin spreads to the central nervous system and binds to gangliosides.(6) There it blocks the release of neurotransmitter from the presynaptic inhibitory neuron.(7) The loss of inhibitory impulses results in the cardinal clinical manifestations of reflex irritability and autonomic hyperactivity.(4) The most common presenting complaints are those of generalized tetanus. After an incubation period of 3 days to 3 weeks, patients complain of dysphagia and stiffness in the jaw, abdomen, or back. As the disease progresses, rigidity and trismus occurs. Generalized rigidity of facial muscles causes the characteristic expression of risus sardonicus. Reflex spasms develop within 1 to 4 days of the first symptoms. Spasm may be precipitated by minimal stimuli such as noise, light, or touch and last from seconds to minutes. They can be painful or dangerous, causing apnea, fractures or rhabdomyolysis.(8)
Ideally, tetanus is treated in an Intensive Care Unit. Managing patients with tetanus in the ICU has significantly reduced the rate of mortality from this disease.(9) The most important early aspects of treatment, after airway protection, is passive immunotherapy with human tetanus immunoglobulin to eliminate as much of the toxin burden as possible. The source of toxin should be eradicated by debridement. Although the disease is caused by the toxin and not active infection, the use of antibiotics may be of help, particularly when there is osteomyelitis. Penicillins are the most frequently used antibiotics although metronidazole may be useful.(10)
Wounds should be debrided to remove foreign bodies and devitalized tissue. Administration of antispasticity agents is the major element of treatment to compensate for the failure of central nervous system inhibition. Finally, supportive care until recovery occurs by the formation of new synapses is essential to minimize the risk of precipitating spasms. The patient's room should be as quiet and dark as possible. Active immunization should be initiated prior to hospital discharge.
Complications and Intensive Care Management:
In severe cases of tetanus, life-threatening respiratory and cardiovascular complications can present with troubling rapidity following the initial diagnosis and admission to the hospital.
One half of mortality associated with tetanus can be attributed to the respiratory complication of the disease.(11-14) Respiratory failure may occur as a result of muscle rigidity and reflex muscle spasm that characterizes the disease or secondary to hypoxia following atelectasis and pneumonia.(1,8) The optimal approach to a tetanic patient with respiratory compromise lies in early intervention with airway and spasm control. Intubation of the trachea should be carried out when maintenance of the airway is in doubt. As the presence of the endotracheal tube is in itself a strong stimulus for spasms, some authors recommend that a tracheotomy be performed immediately.(2,15) The use of mechanical ventilatory support and neuromuscular blocking agents is often required for these patients with impaired ventilatory gas exchange. These patients should be well sedated while paralyzed.(1,2,8,15)
Control of tetanic spasms should be carried out simultaneously as measures are being taken for airway control. The benzodiazepines are the most widely used agents currently available for the control of tetanic spasms and rigidity. These drugs are GABA-A agonists, thereby functioning as indirect antagonists of the effect of the toxin on inhibitory systems.(16-18) Diazepam is used most commonly in managing tetanus in children.(18) Lorazepam may be preferable because of its longer duration of action.(1)
A continuous infusion of midazolam in large doses could also be employed.(20) In our patient, we used a continuous infusion of midazolam for two weeks then replaced it by diazepam via enteral feeding tube. We used diazepam up to 35 mg (1 mg/kg/dose) every 3 hours (280 mg/day). Sedation and amnesia are other properties of benzodiazepines and provide a great value in patients with tetanus.
Propofol has been used as a sedative agent in the Intensive Care Unit.(21,22 ) Limited experience with propofol as a suitable drug for maintaining sedation and muscle relaxation in patients with tetanus is reported.(20,23,24)
Dantrolene, is a direct muscle relaxant which acts at the level of the sarcoplasmic reticulum. This agent may be of value in selected cases.(26,27) When GABA-A agonists are unable to control the muscle spasms, adding neuromuscular blockade to the therapy becomes necessary.(8,20,23) In our patient, we initially used vecuronium at 3.5 mg/hr (0.1 mg/kg/hr) and later switched to pancuronium for cost effectiveness. We increased the dose to 6mg/hr. Interestingly, we were able to wean the patient off neuromuscular blocking agents after we had optimized his diazepam at 35 mg every three hours.
Baclofen is a structural analogue of GABA. When administered intrathecally, baclofen diffuses through the capillaries of the spinal cord, binds to the GABA-B receptors in the substance gelatinosa of the dorsal horn, and inhibits monosynaptic extensor and polysynaptic flexor transmission.(28) Muller, et al. (29) were able to abolish tetanus-induced rigidity and spasms totally by infusion of intrathecal baclofen. Further clinical studies need to be done to prove its effectiveness.
The cardiovascular complications are the most serious complications of tetanus once the airway has been secured.(1) The prevention of death from respiratory causes disclosed the cardiovascular manifestations of tetanus.(30) The pathogenesis of cardiovascular disturbances is postulated to result from the effect of tetanus exotoxin with: (a) brain stem damage resulting in fatal cardiac and respiratory failure,(30) (b) myocardial depression, or toxic myocarditis, believed to be due to excessively high levels of circulating catecholamines,(8,30, 31,32) or (c) widespread disinhibition of autonomic nervous system in the CNS, (31,32) which may lead to the syndrome of sympathetic nervous hyperactivity (5,23,26) and/or parasympathetic overactivity.(31,32)
In 1968 Kerr et al. (33) described the syndrome of sympathetic nervous hyperactivity "sustained but labile hypertension and tachycardia, irregularities of cardiac rhythm, peripheral vascular constriction, profuse sweating, pyrexia, increased carbon dioxide output, increased catecholamine excretion, and in some cases, the late development of hypotension." These signs and symptoms, if they occur, usually develop toward the end of the first week. They may occur spontaneously or in response to minor stimuli, as in the case with tetanus spasms, and cannot be alleviated through pain control or sedation. Most such patients manifest elevated plasma catecholamine levels.(34) Prolonged sympathetic overactivity may end with profound and preterminal hypotension and bradycardia; it often indicates imminent death.(32,35,36) Parasympathetic overactivity may lead to preterminal bradycardia and sinus arrest, salivation and increased bronchial secretions. Direct damage to the vagal nucleus has been implicated,(37) as well as local damage to the sinus node, and to reflex excessive vagal tone.(38)
Prompt recognition and treatment of autonomic dysfunction are important in reducing the mortality in this disease. Clinicians agree that reduced stimulation of patients, if possible, and provision of additional pain relief with narcotic agents should be the first steps. A trial of morphine therapy may be advantageous.(39) Morphine induces a peripheral venous and arteriolar dilation in humans, mediated by a reflex reduction in sympathetic alpha-adrenergic tone.(40) Morphine therapy was used successfully in several cases of generalized tetanus to control autonomic hyperactivity. It has been given in doses of 1-2 mg/kg every 12 hours for 22 days, in one case report, and as a 5-30 mg IV infusion over 30 minutes every 2-8 hours, in a second report.(40,41) Our patient received morphine sulfate as continuous infusion 60 mcg/kg/hr (for 12 hour period) without noticeable effect on hypertension. Only if all this is unsuccessful at controlling the episodes of hypertension should an attempt be made to treat it with other drugs.
Labetalol is both an alpha- and beta-adrenergic blocking agent.(42) It also inhibits the uptake of norepinephrine into nerve terminals. It was used successfully in our patient in controlling the labile hypertension when the combination of heavy sedation, narcotic analgesia, and muscle paralysis failed. Our patient received labetalol initially as intermittent IV boluses 0.25-1.0 mg/kg and was then placed on continuous infusion of 2 mg/kg/hr. The infusion was weaned over four days with no further episodes of hypertension. Similar results were obtained in other cases.(43-45) However, the group from King Edward VIII Hospital, South Africa, have reported a conflicting result.(46) In addition to its favorable side effect profile (47) enough experience in the continuous administration of intravenous labetalol for prolonged period of time has accumulated in children.(48,49) In spite of success of propranolol alone in controlling tachyarrhythmias and hypertension, fatalities associated with its use preclude its use alone for treating this disease.(50,51) The combination of propranolol and alpha blocking agents, such phentolamine and guanethidine, has increased the efficacy with which propranolol lowers blood pressure.(8,31,52) Two recent reports described the successful use of continuous magnesium sulfate infusions to control the autonomic dysfunction of severe tetanus and concluded that this technique is a useful adjunct to sedation, paralysis, and ventilation.(53,54) In other reports, magnesium sulfate did not give adequate control of blood pressure in spite of consistent plasma magnesium level in the recommended range (2.5-4.0 mmol/L).(53-55) In this case adding clonidine, in combination with magnesium, sedation and paralysis, provided better control.(55) The narrow margin between therapeutic toxic blood level of magnesium as well as the need for frequent monitoring of magnesium level may limit its use for this purpose.
Dolar described the use of atropine to control parasympathetic overactivity. Atropine has been employed as a continuous infusion in the treatment of four severe tetanus cases as a supplement to routine therapy. With this treatment his patients maintained complete cardiovascular stability. Further studies are needed to prove its effectiveness in treating severe tetanus patients.(56)
The association between sympathetic overactivity and protein catabolism which subsequently results in inevitable loss of lean body mass in patients severely affected by tetanus was described recently.(57,58) O'Keefe (57) advocates for use of aggressive forms of nutritional support (e.g., total parenteral nutrition including sufficient insulin to maintain normoglycemia) but attempts to provide a large number of calories by using a more dense formulation may be complicated by uncontrollable hyperglycemia and osmotic diarrhea. Linton (59) advocates measuring the actual metabolic rate in individual patients to ensure that an appropriate nutritional regimen is designed. Our patient lost four kilograms during the first week of his hospital stay despite receiving 2,000 kcal/day via nasogastric tube, which was increased to 2,500 kcal/day without any hyperglycemia or diarrhea. Measurement of metabolic rates using an indirect calorimeter device is a reasonable approach. Using readily available high caloric liquid nutrition via enteral feeding tube represents the most appropriate method of meeting the patient's metabolic requirements.
Other secondary complications that have been reported include stress ulcer development, thromboembolism, and skin breakdown. Orthopedic complications include dislocation of the temporomandibular and shoulder joints, myositis ossificans, and vertebral fractures.(8) Rhabdomyolysis, which may produce acute renal failure, is a common complication of generalized tetanus.(1) Pneumonia and sepsis are real threats in today's ICU environment and, if not prevented, recognized, and treated aggressively, could be fatal. Inappropriate anti-diuretic hormone secretion in tetanus may develop.(60) It should resolve with the usual attention to fluid and electrolyte management.
A significant portion of population in the United States and worldwide are inadequately immunized, hence they are at risk for contracting tetanus. Familiarity with tetanus disease, its clinical features, pathogenesis, complications, and principles of management is an important task for every clinician. Any patient, regardless of age or severity of tetanus, has a chance of a full recovery if optimally managed. Our recent experience with use of high dose of benzodiazepines for muscle spasm control and sedation, and use of continuous infusion of labetalol for sympathetic hyperactivity control in a child with severe tetanus was successful. We hope this case will add a current perspective to the pathogenesis and management of severe tetanus.
Consent: As this case occurred about 2 years ago and the family was referred from out-of-state and have since moved, it was not possible to obtain verbal consent for this submission.
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Accepted for publication September 16, 1997
Citation for this article:
Abdelmoneim T, DeNicola LK, Hasan MY. Tetanus: Complications and Management in a Pediatric Intensive Care Unit. in The Rare Case Registry of PedsCCM: The Pediatric Critical Care Web Site, September 16, 1997. Available from: http://pedsccm.org/RARE/Tetanus.html