Current Treatment of Tetanus

Nur Farhanah

Epidemiology

The symptoms described by HippocratesCarle and Rattone in 1884 noticed tetanus in animals by injecting them with pus from a fatal human case.In 1887 Rosenbach detected spores and bacilliIn 1889,Kitasato found bacilli cultureIn 1890 Kitasato and Behring prepared antitoxin In world war I antitetanus serumIn the developing world 50% deathsIn the developed world incidence is low

Tetanus is a vaccine preventable disease

Tetanus is infectious but not contagiousThe prevalencereflects a failure of immunization health care delivery systemNeonatal tetanus eradicated by maternal immunizationHigh risk group are in people who have never been vaccinated, or who completed their childhood series, but did not have a booster dose in the preceding 10 years.

Pathogenesis Tetanus is a toxic infection caused by the obligate anaerobe Clostridium tetani

The spores are very resistant to heat and the usual antiseptics C. tetani cant survive in 121 C for 20 minutes found in the soil and in animal and human intestines

C.tetani is a slender,gram positive,anaerobic rod, develop a terminal spore drumstick appearance

Mode of transmissionContaminated wounds Deep wounds devitalized (dead) tissue Puncture, burn, any break in the skin, and injection-drug sites, mother and newborn child (uterus umilical cord)

PathogenesisC. tetani produces two exotoxins : tetanolysin and tetanospasmin. Tetanolysin (hemolysin) causes damage viable tissue, lowering redox potential optimizing conditions for bacterial multiplication Tetanospasmin (TeTX or TeNT) causes the clinical manifestations of tetanus.

Effect of tetanospasmin

The presynaptic (yellow) neuron of the CNS and the postsynaptic neuron (white). B) Excitatory neurotransmitters potentiating an action potential. C) Inhibitory neurons ready to be released into the synaptic cleft to halt transmission of the action potential. D) Tetanospasmin bound at the presynaptic membrane, preventing the release of the inhibitory motor neurons.

Inhibits the release of GABA and glycine (main transmitter inhibitory system)Symptoms occurAutonomic dysfunction occur some day after onset of spasmActs at the neuromuscular junction where it reduces release of acetylcholine

Effect of tetanospasmin

Clinical FeaturesIncubation period (between exposure to the bacteria in a contaminated wound and development of the initial symptoms) of tetanus 1 day-several months (3-21 days:,rate 8 days)There is a correlation between the distance of the injury from CNS and the duration of incubation periodPeriod of onset : the time between the first symptom and the first reflex spasm

There are 4 clinical form

1.Localized

2.Cephalic

3.Neonatal Rare, mild, potenstial generalizedFixed muscle rigidity,painful spasm in area closer to the site of the injury

Rare,potential generalizedWound to the head /face/chronic otitis media, Atonic palsy motor cranial nerve

Poor sucking, irritability, trismus

4.Generalized Most common form Rigidity and spasm m.masseter trismus (lockjaw) grimace through chenched teeth, close mouth, wrinkled forehead,raised eyebrow (risus sardonicus) neck,thorak ,back ,extremities rigid and spasms (opistotonus) abdominal rigidity

Risus sardonicus Opistotonus

Characteristic of Tetanic spasm:intermitten, irregular, unpredictableTriggered by external stimuli or internal stimuliCognitive function not affected

DiagnosisBased on clinical and symptomsSpatula test in early diagnosisLaboratory test not usually unhelpfulAspirates from wound (gram + bacilli , terminal/subterminal spores)Anaerobic culture rarely positive

Differential Diagnosis of Tetanus

SymptomDDTrismusAlveolar/dental pathologyTemporo-mandibular diseaseNeck stiffnessMuscle spasmMeningitisDysphagiaAcute pharyngeal diseaseSpasmsStrychnine poisoningIntracranial lessionsDrug-induced dystonic reactionsHypocalcemiaNeonatal TetanusSepsisMeningitisConvulsion

Clinical grading /scoring system

SeverityPrognosisDeveloped by Dakar, Phillip, Ablett, Udwadia

Ablett Classification of severity of tetanusGrade I (mild) : trismus with little or no dysphagiaGrade II (moderate) : trismus, dysphagia, generalized muscle rigidity, fleeting spasms, not embarrassing respirationGrade IIIa(severe) : trismus, dysphagia, generalized muscle rigidity, severe spasms, embarrassing respirationGrade IIIb (very severe) Grade IIIa with autonomic dysfunction

Rating Scale for Severity and Prognosis of TetanusScore 1 point for each of the followingIncubation period 120beats/min (neonates >150beats/min)

Total score provides indication of severity and prognosisCephalic tetanus is always scored as severe or very severe

ScoreSeverityMortality0-1Mild50%

Note :There may not be a history of injuryLong incubation period not as guarantee of mild courseThe virulence of the organismThe immune status of the patient

managementNo specific drug can counteract the toxin which bound nervous tissueSpecific treatmentNeutralization of the circulating toxinEradication of the organismSymptomatic TreatmentProtecting the airwaySupportive treatment

Neutralization of the circulating toxinPassive immunization (from human or eguine)Early incubation period toxin circulates in the bloodstreamClinical symptom mostly toxin is bounded to nervous systemAdministration : i.v or IM or intrathecal ? Advantage and Disadvantage

Neutralization of the circulating toxinBest choice : Human Tetanus Immunoglobulin (HTIg) 3000-6000 units IM divided dose ( 40-150UI/Kg of HTIG). -The Optimum dose still in debate -Recommended 500 units -Roncentrations reach peak in 24-48 hr - Long half Life maintained for 10-15 days

Nonavailable HTIg ?

HTIG nonavailable Antitetanus Serum (ATS) - 5001000 IU/kg intravenously or intramuscularly. - 10,000 or 20, 000 units of ATS (5000 U IM and 5000 U infiltrated around the wound) - short half life (2days) - Skin test first - Anaphylactic reactions

The active immunisation is needed active-passive immunisation

TTIgTTIg

Hystory of TT Clean, minor woundsAll other woundsUnknown oe less than 3 dosesYes + NoBasic immYes + yes (250 basic imm IU HTIG or ATS 3000 IUThree or more dosesNo, unless No >10 years since last doseNo,unless No >5y since last dose

Eradicating the organismPenicillin doses is 100 000200 000 IU/kg/day IM/IV for 7 to 10 days - Johnson and Walker study : iv convulsions, focal epilepsy - The structure of penicillin is similar to -aminobutyric acid (GABA) the principal inhibitory neurotransmitter in the CNSPenicillin acts as a competitive antagonist to GABA.side effect of penicillin could synergise with the action of the toxin in blocking transmitter release at GABA neurons.

Metronidazole is a safe alternative- rectal intravenous or intramuscular injections- Salim et al compare penicillin and metronidazole, reduction in mortality in the metronidazole group (7% compared with 24%). - study Yen et al was no significant difference in mortality (penicillin : metronidazole ) - drug of choice in the treatment of tetanus. - Dose 400 mg rectally every 6 hours, or 500 mg every 6 hours intravenously for 710 days.

Other Drugs Erythromycin, tetracycline, vancomycin, clindamycin, doxycycline, and chloramphenicol would be alternatives

Symptomatic Treatment Keys :Control of rigidity and spasmControl of autonomic dysfunction

Control of Rigidity and spasm- Sedation control less severe spasm, not rigidity- Combination drug to control rigidity and spasms- Benzodiazepines and barbiturates GABA agonist, inexpensivePhenobarbital 240mg/8 hoursDiazepam 15-100mg/h i.vMidazolamChlorpromazine 25-50mg/8h is used in combination with GABA agonist

Propofol in severe tetanus Loading dose 50 mg Infusion 3.5-4.5mg/kg/hNo withdrawl, addictionReduction muscle rigidity, rapid recoveryReduces oxygen consumptionCardiovascular instability

Control of Autonomic dysfunctionSympathetic Over Activity (SOA) : tachycardia, depression of bowel motility and bladder function, hypertension, sweatingParasympathetic increase : hypersalivation and bronchial secretionCombined and blockerPropanolol, labetilol, esmololShould be monitor invasive long-term

Suppression of catecholamine releaseMore logical method of controlling SOA Heavy sedation reduce catecholamine level, but interfere cardiac compensatory mechanismMorphine Acts centrally to reduce sympathetic tone in heart and vascular bradycardia, hypotensionInduce peripheral venous and arterial dilatatioDose 240-2500mg/dayIt causes constipation, paralytic ileus

Clonidine - Partial agonist for 2 adrenergic receptors - hypotension by central action as it reduces sympathetic outflow, cathecolamine release and peripherally by inhibiting the release of noradrenaline from the pre-junction nerve ending

Magnesium sulfat is a vasodilatorReduced the release of catecholamine After loading dose 5g bolus over 20mnt , the hourly dose 4-5g/hThe rate of infusion sholud be titrated to control spasm and rigidityMonitor serum Mg, depression of ventilation, the patellar reflex is not valid indicator

Management of TetanusEarly diagnosisNeutralization of unbound toxinTetanus toxoid vaccineEradication of organismTransfer to HNC/ICU/bedside ventilation supportWound debridementTracheostomy (if dysphagia or generalized rigidity)NGT for feedingControl of spasmsControl of Autonomic dysfunctionNutritionGeneral nursing, mouth and tracheostomy care Cornerstones of treatment heavy sedation, muscle paralysis, artificialventilation

complicationIn developed world mortality 20%-40% in severe tetanusDeath complications of treatment cardiovascular complication uncotrolled sympathetic over activity (SOA)In developing world higher mortality method of treatment ICU limited or nonexistent

Key issuesPrompt diagnosis is very crucialPrevention of early complications consists of predicting severity, monitoring the patient, early tracheostomyConventional treatment (heavy sedation, paralysis, artificial ventilation) in ICU not reduced the mortality