Management

Treatment strategies involve three management principles: organisms present in the body should be destroyed to prevent further toxin release; toxin present in the body, outside the CNS should be neutralized; and the effects of toxin already in the CNS should be minimized.

Neutralization of unbound toxin

Human tetanus immune globulin 36000 units is given i.m.2 4 48

Removal of the source of infection

Where present, obvious wounds should be surgically debrided.2 37 48 Penicillin has been widely used for many years but is a GABA antagonist and associated with convulsions.61 Metronidazole is probably the antibiotic of choice. It is safe and comparative studies with penicillin suggest at least as good results.3 121 Erythromycin, tetracycline, chloramphenicol, and clindamycin are all accepted as alternatives.2 4 37 48

Control of rigidity and spasms

Avoidance of unnecessary stimulation is mandatory, but the mainstay of treatment is sedation with a benzodiazepine. Benzodiazepines augment GABA agonism, by inhibiting an endogenous inhibitor at the GABAA receptor. Diazepam may be given by various routes, is cheap and widely used, but long acting metabolites (oxazepam and desmethyldiazepam) may lead to cumulation and prolonged coma. Doses as high as 100 mg h1 have been reported.72 Midazolam has been used with less apparent cumulation.50 Additional sedation may be provided by anticonvulsants, particularly phenobarbitone (which further enhances GABAergic activity)60 and phenothiazines, usually chlorpromazine.25 Propofol has been used for sedation with rapid recovery on stopping the infusion.13 83 When sedation alone is inadequate, neuromuscular blocking agents and intermittent positive pressure ventilation may be required for a prolonged period. Traditionally, the long acting agent pancuronium has been used.36 However, pancuronium inhibits catecholamine reuptake and could worsen autonomic instability in severe cases. There have been isolated reports of worsening hypertension and tachycardia associated with its use.18 40 But Dance reported no difference in complications in those treated with pancuronium compared with other neuromuscular blocking drugs.25 Vecuronium is free from cardiovascular sideeffects and histamine release but is relatively shortacting.40 88 The use of an atracurium infusion in tetanus for 71 days has been reported.81 In this patient, with normal renal and hepatic function, there was no cumulation of laudanosine, the epileptogenic metabolite of atracurium. Longeracting agents are preferable as they lend themselves to administration by intermittent bolus rather than requiring infusion. Prolonged use of aminosteroid neuromuscular blocking agents (vecuronium, pancuronium, rocuronium, and pancuronium), particularly by infusion, has been associated with critical illness neuropathy and myopathy,41 but this has not been reported in tetanus. Of the

newer agents, pipecuronium and rocuronium are long acting clean agents but are expensive. Individual drugs have not been compared in randomized trials. The use of dantrolene to control refractory spasms has been reported in one case.107 Neuromuscular blocking drugs were unnecessary after its administration, paroxysmal spasms stopped and the patients condition improved. Sedation with propofol has allowed control of spasms and rigidity without the use of neuromuscular blocking drugs.13 Examination of the EMG and neuromuscular function during propofol boluses.12 showed an 80% reduction in EMG activity without alteration of function at the neuromuscular junction. However, drug levels were closer to anaesthetic than sedative concentrations and mechanical ventilation would be required. Intrathecal baclofen (a GABAB agonist) has been reported in several small series with varying success.32 92 99 Doses ranged from 500 to 2000 g each day, given as boluses or infusion. Larger doses and boluses were associated with more sideeffects.32 In all the reports, a significant number of patients developed coma and respiratory depression necessitating ventilation.32 99 In some cases, adverse effects were reversible with the GABAA antagonist flumazenil, but this is not reliable.32 The technique is invasive, costly and facilities for artificial ventilation must be immediately available.

Control of autonomic dysfunction

Many different approaches to the treatment of autonomic dysfunction have been reported. Most are presented as case reports or small series. There is a lack of comparative or controlled studies. In general, outcome measures have been limited to haemodynamic data rather than survival or morbidity. Nonpharmacological methods of preventing autonomic instability rely on fluid loading of up to 8 litres day1.66 120 Sedation is often the first treatment. Benzodiazepines, anticonvulsants, and particularly morphine are frequently used. Morphine is particularly beneficial as cardiovascular stability may occur without cardiac compromise.18 93 94 Dosages vary between 20 and 180 mg day1. Proposed mechanisms of action include replacement of endogenous opioids,11 reduction in reflex sympathetic activity and release of histamine.85 Phenothiazines, particularly chlorpromazine are also useful sedatives; anticholinergic and adrenergic antagonism may contribute to cardiovasular stability.58 90 Initially adrenergic blocking agents, such as propranolol, were used to control episodes of hypertension and tachycardia,37 64 90 but profound hypotension, severe pulmonary oedema and sudden death were all found to occur.17 37 58 Labetolol, which has combined and adrenergic blocking effects has been used, but no advantage over propranolol was demonstrated (possibly because its activity is much less than its activity31 34) and mortality remained high.117 In recent years, the shortacting agent, esmolol, has been used successfully.68 Although good cardiovascular stability was achieved, arterial catecholamine concentrations remained elevated.

Sudden cardiac death is a feature of severe tetanus. The cause remains unclear but plausible explanations include sudden loss of sympathetic drive, catecholamineinduced cardiac damage and increased parasympathetic tone or storms. Persisting beta block could exacerbate these causes because of negative inotropism or unopposed vasoconstrictor activity, leading to acute cardiac failure, particularly as sympathetic crises are associated with high systemic vascular resistance and normal or low cardiac output. Isolated use of adrenergic block with long acting agents, therefore, cannot be recommended. Postganglionic and adrenergic blocking agents such as bethanidine, guanethidine, and phentolamine have been successfully used with propranolol,62 90 along with other similar agents such as trimetaphan, phenoxybenzamine, and reserpine.87 A disadvantage of this group of drugs is that induced hypotension may be difficult to reverse, tachyphylaxis occurs and withdrawal can lead to rebound hypertension. The successful management of autonomic disturbance with i.v. atropine has been reported.30 Doses of up to 100 mg h1 were used in four patients. The author argues that tetanus is a disease of acetylcholine excess. He suggests these extremely high doses achieve not only muscarinic but also nicotinic block providing autonomic block, central sedation, and even neuromuscular block. Block of the parasympathetic nervous system was reported to markedly reduce secretions and sweating. The 2adrenergic agonist clonidine has been used orally or parenterally, with variable success. Acting centrally, it reduces sympathetic outflow, thus, reducing arterial pressure, heart rate, and catecholamine release from the adrenal medulla.16 Peripherally, it inhibits the release of norepinephrine from prejunctional nerve endings. Other useful effects include marked sedation and anxiolysis. Two case reports reported opposing results, one with good control105 and one with no alteration in haemodynamic instability.15 Gregorakos used i.v. clonidine 2 g kg1 tds in 17 of 27 patients treated over 12 yr.46 The group randomized to receive clonidine had a significantly lower mortality than those receiving conventional treatment. Epidural49,104 and spinal bupivacaine102 have been reported to reduce cardiovascular instability. However, catecholamine infusions were required to maintain adequate arterial pressure. Magnesium sulphate has been used both in artificially ventilated patients to reduce autonomic disturbance58 72 and in nonventilated patients to control spasms.6 Magnesium is a presynaptic neuromuscular blocker,79 blocks catecholamine release from nerves and adrenal medulla,114 reduces receptor responsiveness to released catecholamines,79 is an anticonvulsant119 and a vasodilator.53 It antagonises calcium in the myocardium and at the neuromuscular junction and inhibits parathyroid hormone release so lowering serum calcium. In overdose, it causes weakness and paralysis,77 with central sedation10 82 although the latter is controversial.58 Hypotension and bradyarrhythmia may occur.73 It is, therefore, mandatory to maintain levels in the therapeutic range. In the report by James and Manson, patients with very severe tetanus were studied and magnesium was found to be inadequate alone as a sedative and relaxant, but an effective adjunct in controlling autonomic disturbance. Serum concentrations were difficult to predict and regular monitoring of serum magnesium and calcium levels were required.58

Muscular weakness was apparent and ventilation was required in all cases. Attygalle and Rodrigo6 studied patients at an earlier stage of the illness yet all cases were probably severe and had undergone tracheostomy. They used similar doses of magnesium to try to avoid sedatives and positive pressure ventilation. They reported successful control of spasms and rigidity. Magnesium concentrations were predictable and readily kept within the therapeutic range, by using the clinical sign of the presence of a patella tendon reflex. In both studies, the absence of hypotension and bradycardia was in contrast to the results with beta block. Both authors agreed that tidal volume and cough may be impaired and secretions increased. Ventilatory support must be immediately available.7 59 More work is necessary on the role of magnesium both with regard to its physiological effect on neuromuscular function in the presence of tetanus and to establish what role, if any, it has in the routine management of severe tetanus. Several drugs show potential for use in the future. Sodium valproate blocks GABA aminotransferase, thereby inhibiting GABA catabolism. In animal studies, this prevents the clinical effects of tetanus toxin.42 Angiotensin converting enzyme inhibitors may also help by inhibiting the synthesis of angiotensin II, which increases norepinephrine synthesis and release from the nerve endings.120 Dexmedetomidine, a more potent 2adrenergic agonist than clonidine, may also have an effect in reducing sympathetic overactivity.87 Finally, adenosine, which reduces presynaptic norepinephrine release and antagonizes the inotropic effects of catecholamines, has theoretical potential.87 To date, its clinical use in this setting has not been discussed.

Supportive intensive care treatment

Weight loss is universal in tetanus.37 Contributory factors include inability to swallow, autonomic induced alterations in gastrointestinal function, increased metabolic rate from pyrexia and muscular activity and prolonged critical illness. Nutrition should, therefore, be established as early as possible. Enteral nutrition is associated with a lower incidence of complications and is cheaper than parenteral nutrition. Percutaneous gastrostomy may avoid the complications associated with nasogastric tube feeding52 and is easily performed on the intensive care unit under sedation. Infective complications of prolonged critical illness including ventilatorassociated pneumonia are common in tetanus.46 112 Securing the airway early in the disease and preventing aspiration and sepsis are logical steps in minimizing this risk. As artificial ventilation is often necessary for several weeks37 tracheostomy is usually performed after intubation. The percutaneous dilatational method20 47 appears particularly suitable for patients with tetanus.29 70 This straightforward bedside procedure avoids transfer to and from the operating theatre with the attendant risk of provoking autonomic instability. Prevention of respiratory complications also involves meticulous mouth care, chest physiotherapy, and regular tracheal suction, particularly as salivation and bronchial secretions are greatly increased. Adequate sedation is mandatory before such interventions in patients at risk of uncontrolled spasms or autonomic disturbance and the balance between physiotherapy and sedation may be difficult to achieve.

Other important measures in the routine management of patients with tetanus, as with any long term critical illness, include prophylaxis of thromboembolism, gastrointestinal haemorrhage, and pressure sores. The importance of psychological support should not be underestimated.

http://bja.oxfordjournals.org/content/87/3/477.long

Approach Considerations
The goals of treatment in patients with tetanus include the following:

Initiating supportive therapy Debriding the wound to eradicate spores and alter conditions for germination Stopping the production of toxin within the wound Neutralizing unbound toxin Controlling disease manifestations Managing complications

Patients should be admitted to an intensive care unit (ICU). If the facility does not have an ICU, the patient should be transferred by critical care ambulance. Passive immunization with human tetanus immune globulin (TIG) shortens the course of tetanus and may lessen its severity. A dose of 500 U may be as effective as larger doses. Therapeutic TIG (3,000-6,000 units as 1 dose) has also been recommended for generalized tetanus.[17] Other treatment measures include ventilatory support, high-calorie nutritional support, and pharmacologic agents that treat reflex muscle spasms, rigidity, tetanic seizures and infections.

Initial Supportive Therapy and Wound Care

Patients should be admitted to the ICU. Because of the risk of reflex spasms, a dark and quiet environment should be maintained. Unnecessary procedures and manipulations should be avoided. Prophylactic intubation should be seriously considered in all patients with moderate-to-severe clinical manifestations. Intubation and ventilation are required in 67% of patients. Attempting endotracheal intubation may induce severe reflex laryngospasm; preparations must be made for emergency surgical airway control. Rapid sequence intubation techniques (eg, with succinylcholine) are recommended to avoid this complication.

Tracheostomy should be performed in patients requiring intubation for more than 10 days. Tracheostomy has also been recommended after onset of the first generalized seizure. The possibility of developing tetanus directly correlates with the characteristics of the wound. Recently acquired wounds with sharp edges that are well vascularized and not contaminated are least likely to develop tetanus. All other wounds are considered predisposed to tetanus. The most susceptible wounds are those that are grossly contaminated or that are caused by blunt trauma or bites. Wounds should be explored, carefully cleansed, and properly debrided. In many cases, the wound responsible for tetanus is clear at presentation, in which case surgical debridement offers no significant benefit. If debridement is indicated, it should be undertaken after the patient has been stabilized. The current recommendation is to excise at least 2 cm of normal viable-appearing tissue around the wound margins. Abscesses should be incised and drained. Because of the risk of releasing tetanospasmin into the bloodstream, any wound manipulation should be delayed until several hours after administration of antitoxin.

Pharmacologic Therapy
Elimination of toxin production
Antimicrobials are used to decrease the number of vegetative forms of C tetani (the toxin source) in the wound. For years, penicillin G was used widely for this purpose, but it is not the current drug of choice. Metronidazole (eg, 0.5 g every 6 hours) has comparable or better antimicrobial activity, and penicillin is a known antagonist of gamma-aminobutyric acid (GABA), as is tetanus toxin. Metronidazole may also be associated with lower mortality.[18] Other antimicrobials that have been used are clindamycin, erythromycin, tetracycline, and vancomycin.

Neutralization of unbound toxin

Tetanus immune globulin (TIG) is recommended for treatment of tetanus. It should be kept in mind that TIG can only help remove unbound tetanus toxin; it cannot affect toxin bound to nerve endings. A single intramuscular (IM) dose of 3000-5000 units is generally recommended for children and adults, with part of the dose infiltrated around the wound if it can be identified. The World Health Organization recommends TIG 500 units by IM injection or intravenously (IV)depending on the available preparationas soon as possible; in addition, 0.5 mL of an age-appropriate tetanus toxoidcontaining vaccine (Td, Tdap, DT, DPT, DTaP, or tetanus toxoid, depending on age or allergies), should be administered by IM injection at a separate site. Tetanus disease does not induce immunity; patients without a history of primary tetanus toxoid vaccination should receive a second dose 1-2 months after the first dose and a third dose 6-12 months later.

Control of disease manifestations

Benzodiazepines have emerged as the mainstay of symptomatic therapy for tetanus. Diazepam is the most frequently studied and used drug; it reduces anxiety, produces sedation, and relaxes muscles. Lorazepam is an effective alternative. High dosages of either may be required (up to 600 mg/day). To prevent spasms that last longer than 5-10 seconds, administer diazepam IV, typically 10-40 mg every 1-8 hours. Vecuronium (by continuous infusion) or pancuronium (by intermittent injection) are adequate alternatives. Midazolam 5-15 mg/hr IV has been used. If the spasms are not controlled with benzodiazepines, long-term neuromuscular blockade is required. Phenobarbital is another anticonvulsant that may be used to prolong the effects of diazepam. Phenobarbital is also used to treat severe muscle spasms and provide sedation when neuromuscular blocking agents are used. Other agents used for spasm control include baclofen, dantrolene, short-acting barbiturates, and chlorpromazine. Propofol has been suggested for sedation.[19] Intrathecal (IT) baclofen, a centrally acting muscle relaxant, has been used experimentally to wean patients off the ventilator and to stop diazepam infusion. IT baclofen is 600 times more potent than oral baclofen. Repeated IT injections have been efficacious in limiting duration of artificial ventilation or preventing intubation. Case reports and small case series have suggested that IT baclofen is effective in controlling muscle rigidity,[20, 21] though others have questioned this.[22] The effects of baclofen begin within 1-2 hours and persist for 12-48 hours. The half-life elimination of baclofen in cerebrospinal fluid (CSF) ranges from 0.9 to 5 hours. After lumbar IT administration, the cervical-to-lumbar concentration ratio is 1:4. The major adverse effect is a depressed level of consciousness and respiratory compromise.

Management of complications
Specific therapy for autonomic system complications and control of spasms should be initiated. [23] Magnesium sulfate can be used alone or in combination with benzodiazepines for this purpose. It should be given IV in a loading dose of 5 g (or 75 mg/kg), followed by continuous infusion at a rate of 2-3 g/h until spasm control is achieved.[5] The patellar reflex should be monitored; areflexia (absence of the patellar reflex) occurs at the upper end of the therapeutic range (4 mmol/L). If areflexia develops, the dosage should be reduced. An infusion of magnesium sulfate does not reduce the need for mechanical ventilation in adults with severe tetanus, but it does reduce the requirement for other drugs to control muscle spasms and cardiovascular instability.[24] In a meta-analysis of 3 controlled trials that compared magnesium sulfate with placebo or diazepam for the treatment of patients with tetanus, magnesium sulfate did not reduce mortality or relative risk.[25] The investigators concluded that further controlled trials were necessary to

evaluate the potential effect of this therapy on autonomic dysfunction, spasms, length of ICU and hospital stay, and requirement for mechanical ventilation. Morphine is an option. In the past, beta blockers were used, but they can cause hypotension and sudden death; only esmolol is currently recommended. Hypotension requires fluid replacement and dopamine or norepinephrine administration. Parasympathetic overactivity is rare, but if bradycardia is sustained, a pacemaker may be needed. Clinical tetanus does not induce immunity against future attacks; therefore, all patients should be fully immunized with tetanus toxoid during the convalescent period.

http://emedicine.medscape.com/article/229594-treatment#aw2aab6b6b4

Prevention and Treatment

The tetanus toxoida version of the toxin inactivated by formalinwas first produced in 1924, and widespread vaccination in developed countries began a few decades later. Vaccination is incredibly effective at preventing tetanus. Those who do develop tetanus, however, must receive immediate treatment. Three management principles are used in the treatment of tetanus: C. tetani organisms present in the body should be destroyed to prevent the release of more toxin; toxin already released should be neutralized, if possible; and the effects of toxin already in the CNS should be minimized (Cook 2001).

Vaccination
There are currently four vaccine preparations containing the tetanus toxoid: DTaP, DT, Tdap, and Td (D = diphtheria, T = tetanus, and aP = acellular pertussis). Capital letters in the abbreviation stand for full-strength toxoid and lowercase letters stand for a reduced-strength toxoid. DTaP and DT are meant for children younger than 7 years old. Tdap and Td are for adolescents and adults (CDC Vaccines). After receiving primary doses of the vaccine, antitoxin levels greatly exceed the protective levels of 0.1 IU/mL. Antitoxin levels decrease over time, however, and a booster should be given every 10 years. It is also recommended that anyone who receives a wound that is neither clean nor minor and has not had a booster in more than five years should receive one (Pink Book). The vaccine is nearly 100% effective in preventing tetanus, though it is not perfect. In one case, a man with antitetanus antibody levels of 0.22 IU/mL developed rigidity and autonomic dysfunction and responded positively to treatment for tetanus (Beltran 2007).

Treating the Infection

The first two principles of tetanus treatment involve neutralizing the unbound toxin and removing the source of infection. The unbound toxin is neutralized using human tetanus immunoglobulin (HTIG). HTIG is injected intramuscularly in doses ranging from 500-10,000 IU, though 500 IU is now the preferred dose (Hsu 2001). Due to the high binding affinity of TeTx to substrates in neurons, HTIG can only neutralize the unbound toxin circulating outside of neurons. The source of infection must be eliminated in order to prevent the release of more TeTx. If a wound is present it should be cleaned and all devitalized tissue should be removed. Cleaning the wound decreases the bacterial load directly, and, as C. tetani is an obligate anaerobe, exposing the infection to the air will help kill some bacteria (Cook 2001; Hsu 2001). Antibiotics must also be used to destroy any more C. tetani that may produce toxin. Penicillin, metronidazole, erythromycin, tetracycline, chloramphenicol, and clindamycin are all acceptable for use. In one of the few studies to directly test antibiotic sensitivity in C. tetani cultures, it was shown that strains taken from dozens of clinical tetanus patients were sensitive to penicillin, metronidazole, chloramphenicol, erythromycin, and ofloxacin, but were resistant to trimethoprim/sulfamethoxazole (Figure 7; Campbell 2009). As seen in Figure 7, penicillin and metronidazole had the largest clearings at 42 mm. Erythromycin produced the largest minimum clearing around the antibiotic disk, but both penicillin and metronidazole still had relatively large minimum clearings. These results, taken with historical treatment practices, led the researchers to conclude that penicillin is an appropriate treatment against C. tetani, with metronidazole being a suitable alternative.

Figure 7. Antibiotic sensitivities of 45 clinical C. tetani isolates. Overall, the C. tetani strains were most sensitive to penicillin and metronidazole, and were only resistant to the trimethoprim/sulfamethoxazole mix (from Campbell 2009).

Though penicillin was the drug of choice to treat tetanus infection in the past, other researchers recommend the use of metronidazole (Cook 2001; Hsu 2001). Metronidazole is associated with a better recovery time and a lower mortality rate than penicillin. Penicillin requires adequate blood flow to the site of infection in order to reach effective concentrations. The anaerobic wounds where C. tetani thrive often have become devitalized and do not receive enough blood flow.

Metronidazole can penetrate devitalized tissue in wounds that penicillin cannot normally reach (Ahamdsyah 1985). Thus, while penicillin and metronidazole may have similar effectiveness in C. tetani cultures, they can produce different results in actual patients. Campbell et al. (2009) have suggested the use of topical instead of intravenous penicillin to avoid these vascularization issues. However, penicillin still has the added disadvantage of being a GABAA receptor antagonist; given that tetanus acts mainly by antagonizing the release of GABA in the CNS, it would seem unwise to compound that effect during treatment (Bleck 1994). With greater effectiveness and fewer side effects, metronidazole appears to be a better treatment against C. tetani infection in tetanus patients.

Treating the Symptoms

The third major part of treatment for tetanus is controlling the effects produced by toxin already bound to substrates in the CNS. The three main categories of symptomsrigidity, muscle spasms, and autonomic dysfunctionmust all be treated to avoid potentially fatal complications and to improve the general well-being of patients. Muscle spasms and rigidity can often be controlled with the use of drugs that agonize GABAergic neurons and systems. Benzodiazepines are the drug of choice for control of muscle spasms. Drugs such as diazepam and midazolam have been used successfully to reduce muscle spasms and induce sedation (Hsu 2001; Cook 2001). Benzodiazepines bind to GABA receptors and facilitate the binding of GABA, which helps increase the action of GABA on post-synaptic target neurons (Julien 2008). If benzodiazepines are not sufficient, neuromuscular blocking agents, such as vecuronium, may be required. Paralytics like these require mechanical ventilation (Hsu 2001; Cook 2001). Additional sedation can be achieved with the barbiturate phenobarbital or the typical antipsychotic chlorpromazine (Cook 2001). Barbiturates, like benzodiazepines, are GABA agonists. Unlike benzodiazepines, however, barbiturates not only facilitate the binding of GABA with its receptor, but they can also open GABA chloride ion channels in the absence of the neurotransmitter itself (Julien 2008). Because GABA release is being blocked by TeTx, it may be useful to use drugs that can control muscle spasms in the absence of GABA. Autonomic dysfunction has proven more difficult to control. Alpha- and beta-adrenergic blockers have been used to counter hypertension and cardiac problems. Both classes of drugs, however, have been associated with worsening symptoms or even sudden death (Cook 2001). Other agents that modulate output from the SNS have been used with mixed results. Clonidine, an alpha-adrenergic agonist, may reduce sympathetic output and thus reduce arterial pressure, heart rate, and catecholamine release, but case reports show conflicting results (Cook 2001). Magnesium may also help by blocking release of catecholamines, though the results again are mixed (Hsu 2001). One study found that magnesium sulfate treatment did not lower the number of patients requiring mechanical ventilation, but it did lower the amount of other drugs needed to control muscle spasms and cardiovascular instability, such as midazolam and verapamil (Thwaites 2006). The opioid-analgesic drugs morphine and fentanyl may also help decrease output of the SNS by modulating central controls (Hsu 2001; Cook 2001). Opioids decrease blood pressure and cause peripheral vasodilation (Julien 2008).
http://microbewiki.kenyon.edu/index.php/Clostridium_tetani_and_Tetanus