Jurding Syaraf (Fatimah NJ – 1610221007)

  

“Evaluation of beneficial effects of addition of intramuscular human tetanus

immunoglobulin to intrathecal therapy in the

treatment of tetanus”

Diajukan Untuk Memenuhi Syarat Mengikuti Ujian Kepaniteraan Klinik di Bagian Saraf

  

Diajukan Kepada:

Pembimbing: dr. Nurtakdir Kurnia Setiawan, Sp.S, MSc

Disusun Oleh:

Fatimah Nur Janah 1610221007

  

KEPANITERAAN KLINIK DEPARTEMEN ILMU PENYAKIT SARAF

FAKULTAS KEDOKTERAN

UNIVERSITAS PEMBANGUNAN NASIONAL “VETERAN” JAKARTA

RUMAH SAKIT UMUM DAERAH AMBARAWA

  

2018

Research Article

  Department of Medicine, Mahatma Gandhi Memorial Medical College, Indore, Madhya Pradesh, India

  Received: 26 December 2015 Accepted: 15 January 2016

  International Journal of Advances in Medicine Mahajan S. Int J Adv Med. 2016 Feb;3(1):110-115 pISSN 2349-3925 | eISSN 2349-3933

  

Sanjiv Mahajan*

  

Evaluation of beneficial effects of addition of intramuscular human

tetanus immunoglobulin to intrathecal therapy in the

treatment of tetanus

• *Correspondence:

  

Methods: 125 patients of tetanus were randomized to two groups. Study group was given

intrathecal plus intramuscular HTIg while control group was given intrathecal HTIg alone. Each

group was subdivided into three grades according to severity. Mortality rate and three sequential

recovery parameters i.e. duration of spasms, shift to oral therapy and duration of hospital stay

were measured.

  

Results: No signifcant difference in mortality was found. However, in patients who survived, the

addition of intramuscular HTIg lead to a beneft of 2.07, 2.67 & 2.31 days in mild, moderate &

severe grades respectively in the duration of spasms. Further, it became possible to start oral

therapy 2.13, 1.6 & 1.8 days earlier in mild, moderate & severe tetanus. Duration of hospital stay

was reduced by 3.87 days, 2.36 days and 3 days in mild, moderate and severe tetanus

respectively.

  ABSTRACT

Background: The treatment of tetanus has evolved from supportive management only to

specifc treatment to neutralize the tetanus toxins – tetanospasmin & tetanolysin. Human

Tetanus Immunoglobulin (HTIg) is a large molecule and cannot cross the blood brain barrier.

Introduction of intrathecal therapy considerably decreased mortality in the disease. Combined

administration of intramuscular and intrathecal HTIg should neutralize the tetanus toxins in the

circulation and central nervous system simultaneously. The study was done to detect benefcial

effects of adding intramuscular HTIg to the intrathecal therapy.

  article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access

  INTRODUCTION

  The earliest record of tetanus is in Edwin Smith Surgical

  Papyurs, supposed to be dated 19 ^th Century B.C.

  ‘bahirayamma'. Charak observed that it was due to

  provoked wind drying up the external nerves of the back DOI:

  Dr. Sanjiv Mahajan, E-mail:

  

Conclusions: Though the addition of intramuscular HTIg to intrathecal therapy in tetanus does not confer any survival beneft, it causes faster recovery in patients who survive.

Keywords: Human tetanus immunoglobulin, Intramuscular, Intrathecal, Oral therapy, Spasms, Tetanus and the nape of' the neck. He further recorded that either the disease killed the patient or caused deformity. Greek physician Aretaeus in first century A.D. mentioned it as "An inhuman calamity, an unseemly sight, a spectacle painful even to behold".

  Sir Charles reported a case of tetanus in London. Pollack from Dalin reported a similar case. Bose gave first comprehensive description of the disease. Nicoliers produced tetanus by injecting animals with garden soil. His subsequent description of the bacillus obtained from

  

Mahajan S. Int J Adv Med. 2016 Feb;3(1):110-115

  the site of injection resembled Clostridium tetani. Isolation of micro-organism, clostridium, was done in pure culture by Kitasato. Ehelich separated two distinct and different toxins - Tetanospasmin and Tetanolysin. Marier and Morax and Meyer & Ransom observed the central action of toxin. Tulloch observed different serologic types of the bacillus.

  Until 19th century, the treatment was mainly based on volatile general anaesthesia. The physicians relied chiefly on opium and a variety of strange methods in an attempt to arrest the disease. The first hint of rational therapeutic approach came with introduction of the muscle paralysing effect of crude curare preparations from South America. Sir Benjamin Collins Brodie showed that artificial respiration and bellows preserved the life of curarised animals. ¹ Collen used large doses of opium and also recommended the frequent use of laxatives. O'Beirne treated 20 patients of tetanus with tobacco, gum elastic tube and croton oil. He claimed success in 11 of them. ² Von Bellin and Kitasato did successful immunization against tetanus. ³ Ramon introduced tetanus toxoid

  ‘anatoxine tétanique’ as a prophylactic tool in order to prevent the tetanus disease in pets (with P. Descombey) and in humans (with Ch. Zoeller). ⁴ Clostridium tetani is a gram positive, anaerobic, spore forming bacillus which produces devastating toxins, second only to botulinum in toxicity. The two important toxins produced by Cl. Tetani are tetanospasmin and tetanolysin. Tetanospasmin targets the somatic nerves and causes muscular tension and spasm by blocking the release of the inhibitory neurotransmitters glycine and gamma aminobutyric acid. Tetanolysin similarly inhibits the controlling mechanisms of autonomic nerves, resulting in a labile cardiovascular system, unpredictable respiratory function, sweating, hyperpyrexia and other symptoms of autonomic dysfunction.

  The toxins released by the maturing bacilli, are taken up by the lymphatic and vascular circulations and distributed to the endplates of all nerves. This results in a virtual simultaneous uptake of the toxins by all nerves, which then conduct them centripetally to the central nervous system. The rate of transmission is fastest along the sensory and slowest along adrenergic neurons, but the greatest quantity is conducted by motor neurons. The shortest nerves are first to deliver the toxins which give rise to the usual early symptoms of back and neck stiffness and facial distortion. As the toxins are delivered to the spinal cord by the longer nerves, motor nerves are affected sequentially according to their length until all muscles become devoid of central nervous system (CNS) control and contract or go into spasm. Autonomic dysfunction becomes progressively evident as the level of CNS intoxication increases. Local tetanus is the exception to the normal spread of the toxins. It results from the lone intoxication of nerve endings at the site of

  The severity of signs and symptoms is directly related to the concentration of the toxin discharged into the blood stream and being transmitted by the nerves to the spinal cord. It is therefore vital to neutralize the toxins in the circulation before they are taken up by the nerves, and equally imperative to neutralize the toxins in cerebrospinal fluid (CSF) before they become fixed to the neurons. Elimination of the toxin in the circulation still leaves toxins passing along the nerves. Once the toxin becomes fixed, it cannot be dislodged. Its effect can only be minimized or prevented. Conservative management of tetanus consists of good nursing care, keeping the patient in a quiet environment, antibiotics to counter the infection, sedatives and muscle relaxants. The specific management of tetanus is to neutralize unbound toxin by giving antitoxin along with life support.

  The first antitoxin used was Antitetanus Serum (ATS) derived from horse serum. Due to the severe anaphylactic reactions it produced, it was superseded by Human Tetanus Immunoglobulin (HTIg) made from human sera. Tetanus Immunoglobulin was initially given by intramuscular route. It was postulated that being a large molecule, most of Tetanus Immunoglobulin cannot cross the blood-brain barrier and neutralize the toxin in the central nervous system. Ildrim was the first to observe the superiority of intrathecal ATS over intramuscular ATS. ⁵ But in 1979,

  Sedaghatian observed that the mortality rate and duration of hospital stay were not significantly different when intrathecal therapy is given compared to intramuscular therapy. ⁶ Vakil found no significant difference between intrathecal and intravenous groups. ⁷ Opposite views came out in the studies of Bhandari which showed that intrathecal therapy lead to higher mortality than intramuscular therapy while Mongi showed that intrathecal therapy was superior to intramuscular in the treatment of neonatal tetanus. ^8,9 Menon also observed the superiority of intrathecal treatment. ¹⁰ In 2004, Miranda-Filho and colleagues compared the efficacy of intramuscular HTIg (3,000 IU) plus intrathecal HTIg (1,000 IU) with intramuscular HTIg alone and found no significant difference in mortality. ¹¹ But a significant improvement was observed in the treatment group with regard to spasms and duration of hospital stay. Ahmad and colleagues found a significant mortality benefit and a shorter hospital stay when intrathecal HTIg was given for neonatal tetanus. ¹² In the first meta-analysis of intrathecal vs intramuscular therapy trials done by Abrutyn, no benefit of intrathecal serotherapy was found. ¹³ However not all trials in the meta-analysis were randomized. A meta-analysis of also found a significant benefit of using high dose (>250

  IU) of intrathecal treatment. The maximum dose of intrathecal treatment was 1500 IU. The present opinion is that intrathecal treatment is more effective than intramuscular treatment in the management of tetanus. Apart from intrathecal vs intramuscular route, intrathecal route has been compared with intravenous route and intrathecal plus intramuscular route has been compared with intramuscular route. However, there has been no study till date which explored the possibility of beneficial effect of adding intramuscular dose to the intrathecal therapy. The present study was undertaken to gauge whether any beneficial effects in the form of decreased mortality or faster recovery occur on adding intramuscular therapy of HTIg to the intrathecal therapy. It is postulated that while the intrathecal route neutralizes the toxins in the CSF, the toxins are still present in the circulation on which the intrathecal route is ineffective. The addition of intramuscular therapy should have an additive beneficial effect. The recovery parameters used in previous trials i.e. ‘duration of spasms’ and ‘duration of hospital stay’ were compared in the present study. Apart from these, ‘shift to oral therapy’ was also used as a recovery parameter for the first time in any study.

  METHODS 125 patients of tetanus were included in the study.

  Informed consent was taken from the patients. Those who agreed to participate in the study were randomized to two groups. 65 cases were allocated to the study group and 60 cases were allocated to the control group. Study group patients were given intrathecal plus intramuscular HTIg. These were compared with a control group consisting of 60 patients that were given intrathecal HTIg alone. Supportive treatment was similar in both the groups. In the study group patients, a lumbar puncture was done under strict aseptic care and 2 ml of CSF taken out. Then HTIg was injected intrathecally. The puncture site was sealed properly. Simultaneously HTIg was injected intramuscularly. The dosages of HTIg in IU were as follows: 2-5 years - intrathecal 500 plus intramuscular 500, 5-10 years - intrathecal 1000 plus intramuscular 750, >10 years - intrathecal 1500 plus intramuscular 1000. In the control group, only intrathecal administration of HTIg as sited above was carried out. All patients were given routine regimen of injection Penicillin, Diazepam, Methocarbamol, Chlorpromazine, etc. Patients below 2 years or above 70 years of age and those who died within 12 hours of admission were excluded from the study. Five criteria were used in grading the severity of the disease. Criterion (C) – 1: Lockjaw, C-2: Spasms, C-3: Incubation period of 7 days or less, C-4: Period of onset of spasms of 48 hours or less, C-5: Fever defined as

  This grading has been modified from criteria devised by Patel and Joag. ¹⁵ The grading was done as follows:  Mild: Only one or two of the five criteria, generally

  C-1and/or C-2. Occasionally fever (C-5) with C-1 or C-2.  Moderate: Consisted of three of the five criteria, i.e.

  C-1 + C-2 and any one of the other three criteria.  Severe: Consisted of at least four of the five criteria. A comparative study between each corresponding grade of the two groups was carried out regarding the survival rate, duration of persistence of spasms, shift to oral therapy, duration of hospital stay and any side effects. Fisher Exact Test was used for comparison of mortality. Continuous variable data was compared by independent t-test and reported as mean ± standard deviation (SD). p < 0.05 was considered significant.

  RESULTS The mortality was nil in mild tetanus in both the groups.

  No significant difference in mortality was found due to addition of intramuscular HTIg in moderate and severe tetanus (Table 1). Overall mortality was 15.38% in study group which was not significantly different from the standardized mortality for severity of the control group which was 14.88% (Table 1a).

  Addition of intramuscular HTIg had a significant effect on the duration of spasms in mild, moderate and severe tetanus (Table 2). Spasms persisted for only an average of 0.33 days in mild tetanus in study group compared to 2.4 days in control group. In moderate & severe tetanus, the difference was very highly significant. The spasms lasted only an average of 1 day in moderate tetanus in study group compared to 3.67 days in control group. In severe tetanus they lasted for an average of 1.45 days & 3.76 days in study and control groups respectively. Addition of intramuscular HTIg also facilitated earlier shift to oral therapy (Table 3) which was an average of 5.08 days in mild tetanus in study group compared to 7.21 days in control group. In moderate tetanus shift to oral therapy occurred in 5.9 days in study group while it was 7.5 days in control group. In severe tetanus, the oral therapy was started in 8.61 days in study group and 10.41 days in control group. All the differences were statistically significant.

  Overall benefit was also found in duration of hospital tetanus. This was earlier than in control group which moderate tetanus and 18.82 days in severe tetanus. ranged from 14.79 days in mild tetanus, 15.06 days in No side effects of HTIg were observed in either group.

  

Table 1: Comparison of mortality rates in study and control groups.

  Study group Control group

  Severity Patients Expired Mortality (%) Patients Expired Mortality (%) Mild

  12

  19 Moderate

  11

  1

  9.09

  19

  1

  5.26 Severe

  42

  9

  21.43

  22

  5

  22.73 Total

  65

  10

  15.38

  60

  6

  10.00 Fisher test statistic value =1, not significant

  Table 1A: Standardized mortality of control group vis ₁₆ IU of intrathecal HTIg. Miranda-Filho et al could a vis study group.

  decrease the mortality to 7% when they added a dose of 1000 IU of intrathecal HTIg to 3000 IU of intramuscular

  Study group Control group (Standardized)

  HTIg while comparing it with intramuscular dose only. In

  Mortality (%) 15.38

  14.88

  their group, most of the patients were having mild to

  Fisher test statistic value =1, not significant

  moderate tetanus. In the present study, 1500 IU of intrathecal HTIg was used in patients over 10 years of

  Table 2: Mean duration of persistence of spasms (in

  age. The total mortality was 15.38% in the study group days). having a majority proportion of patients having severe tetanus. Thus the study reconfirms the mortality benefit

  Study group Control group p value of using higher doses of intrathecal HTIg.

  Mild 0.33 ± 0.3 2.4 ± 1.27 0.035 Moderate 1 ± 0.34 3.67 ± 1.53 <0.0001 Severe 1.45 ± 1.19 3.76 ± 2.31 <0.001 The study found no survival benefit of adding intramuscular HTIg to intrathecal therapy. However, the benefit of adding intramuscular HTIg occurred in patients Table 3: Comparison of shift to oral therapy (in days). who survived and resulted in faster recovery. In these

  Study group Control group p value patients, intramuscular HTIg significantly reduced

  Mild 5.08 ± 3.23 7.21 ± 2.76 0.034 duration of spasms. The benefit of adding intramuscular Moderate 5.9 ± 2.91 7.5 ± 1.71 0.044 therapy was seen in all subgroups as spasms lasted for a Severe 8.61 ± 3.04 10.41 ± 3.34 0.033 mean duration of 0.33, 1 & 1.45 days in mild, moderate

  & severe tetanus respectively. This translated into a benefit of more than 2 days in all subgroups as spasms

  Table 4: Mean duration of hospital stay (in days).

  were controlled 2.07, 2.67 & 2.31 days earlier in the

  Study group Control group p value mild, moderate & severe grades respectively of the study

  Mild 10.92 ± 5.98 14.79 ± 5.32 0.04 group. Moderate 12.7 ± 3.77 15.06 ± 3.76 0.069 Severe 15.82 ± 3.55 18.82 ± 8.05

  0.04 Though spasm is a reliable indicator in tetanus, there is no published study which has documented the mean duration of spasms. However the study by Miranda-Filho

  DISCUSSION

  et al (vide supra) has commented that in patients in whom spasms were controlled in less than 10 days, 68% were The introduction of intrathecal therapy has considerably those receiving intrathecal plus intramuscular HTIg while reduced mortality in tetanus and has now become standard therapy in many centres. Even after reduction, 32% were those receiving intramuscular HTIg. the mortality is considerable in severe tetanus. In the

  The benefit of adding intramuscular HTIg continued after present study, mortality was nil in mild tetanus in both study and control groups while it was 9.09% & 5.26% control of spasms as it was possible to shift these patients to oral therapy earlier. It was possible to start oral therapy respectively in moderate tetanus. In severe tetanus, the corresponding figures were 21.43% & 22.73%. 2.13 days earlier in mild tetanus, 1.6 days earlier in moderate tetanus and 1.8 days earlier in severe tetanus with all the differences assuming significant value. ‘Shift

  Agarwal M et al observed a mortality of 20% in mild process occurring between control of spasms and discharge from hospital. Ultimately, the earlier control of spasms and an earlier shift to oral therapy in the study group had an amplifying benefit on the duration of hospital stay. In the study group, patients with mild, moderate and severe tetanus had a mean duration of hospital stay of 10.92 days, 12.7 days and 15.82 days respectively. Patients in the study group with mild tetanus were discharged 3.87 days earlier while those with moderate and severe tetanus were discharged 2.36 days and 3 days earlier respectively. The study by Agarwal M et al. (vide supra) reported a mean duration of 12.3 days in mild tetanus and 29 days in severe tetanus patients receiving intrathecal therapy though the study had only 8 & 3 patients respectively in the above groups. The study by Miranda-Filho et al. (vide supra) had observed a reduction in duration of hospital stay in patients receiving intrathecal therapy with 43% of patients being discharged within 15 days as compared to 27% of patients being discharged within 15 days in intramuscular group. The present study suggests a further reduction in hospital stay when intramuscular HTIg is added to intrathecal therapy. In the present study, no side effects of HTIg were observed in either group. Most of the other clinical trials had also not reported any side effects of HTIg though Robert et al. reported reversible paraplegia after high dose of intrathecal human immunoglobulin. ¹⁷ Thus the benefit of adding intramuscular HTIg was found in all three parameters observed. It causes faster recovery of the patients and thus reduces hospital burden. An explanation of the benefit may be suggested. While intrathecal HTIg neutralizes the tetanus toxin in the CSF, the intramuscular dose neutralizes it in the circulation before it is taken up by the nerves. Thus the combined administration neutralizes the toxins more effectively. However, in patients who succumb to the disease, most of the toxin is already fixed and cannot be neutralized. Hence addition of intramuscular therapy is not helpful in reducing mortality.

  CONCLUSIONS

  9. Mongi PS, Mbise RL, Msengi AE, Do Amsi DM.

  15. Patel JC, Joag GG. Grading of tetanus to evaluate prognosis. Indian J Med Sci. 1959;13:834-40.

  Intrathecal vs. intramuscular administration of human antitetanus immunoglobulin or equine tetanus antitoxin in the treatment of tetanus: A meta- analysis. Trop Med Int Health. 2006;11:1075-81.

  14. Kabura L, Ilibagiza D, Menten J, Van den Ende J.

  13. Abrutyn E, Berlin JA. Intrathecal therapy in tetanus: A meta-analysis. JAMA. 1991;266:2262-7.

  12. Ahmad A, Qaisar I, Naeem M, Mazhar AU, Ashfaq M. Intrathecal antitetanus human immunoglobulin in the treatment of neonatal tetanus. J Coll Physicians Surg Pak. 2011;21:539-41.

  11. Miranda-Filho Dde B, Ximenes RA, Barone AA, Vaz VL, Vieira AG, Albuquerque VM. Randomised controlled trial of tetanus treatment with antitetanus immunoglobulin by the intrathecal or intramuscular route. BMJ. 2004;328:615-9.

  2002;39:654-7.

  10. Menon J, Mathews L. Intrathecal immunoglobulin in the treatment of tetanus. Indian Pediatr.

  Tetanus neonatorum – experience with intrathecal serotherapy at Muhimbili Medical Centre, Dar es Salaam, Tanzania. Ann Trop Paediatr. 1987;7:27- 31.

  8. Bhandari B, Ajmera NK, Jagetiya PR. Intrathecal antitetanus serum in management of tetanus neonatorum. Indian J Med Res. 1980;72:685-7.

  The addition of intramuscular HTIg to intrathecal therapy in tetanus does not confer any survival benefit. However, the benefit of combined administration occurs in patients who survive and manifests by faster recovery. It causes earlier control of spasms, earlier shift to oral therapy, and reduced duration of hospital stay and is without any side effects.

  Therapeutic trial of intracisternal human tetanus immunoglobulin in clinical tetanus. Trans R Soc Trop Med Hyg. 1979;73:579-83.

  7. Vakil BJ, Armitage P, Clifford RE, Laurence DR.

  1979;54:623-5.

  6. Sedaghatian MR. Intrathecal serotherapy in neonatal tetanus: a controlled trial. Arch Dis Child.

  5. Ildirim I. A new treatment for neonatal tetanus - antitetanic serum and prednisolone given together intrathecally. The Turk J Pediatr. 1967;9:89-95

  4. Ramon G. Notice des titres et travaux scientifiques de G. Ramon, Paris. Ancienne imprimerie de la Cour d'Appel. 1934:109.

  3. Von Behring E, Kitasato S. Ueber das Zustandekommen der Diphtherie-Immunität und der Tetanus-Immunität bei Thieren. Dtsch Med Wochenschr. 1890;16(49):1113-4.

  2. O'Beirne J. Abstract of a communication on tetanus or locked-jaw. Lancet. 1836;26(680):826-7.

  1. Brodie BC. Experiments and observations on the different modes in which death is produced by certain vegetable poisons. Phil Trans Roy Soc. 1811;101:178-208.

  Funding: No funding sources Conflict of interest: None declared REFERENCES

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  17. Robert R, Rouffineau J,

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  Cremault A. Paraplegie benefcial effects of addition of intramuscular reversible apre` injection human tetanus immunoglobulin to intrathecal intrathecale de fortes therapy in the treatment of tetanus. Int J Adv doses de

Med 2016;3:110-5 gammaglobulines

  humaines lors du traitement de tetanos de faible gravite´. Quatre observations. La Presse Medicale. 1984;13:1947- 79.

  

Evaluasi efek menguntungkan dari penambahan

imunoglobulin tetanus intramuskular manusia ke terapi

intratekal dalam pengobatan tetanus

ABSTRAK

  

Latar belakang: Pengobatan tetanus telah berevolusi dari manajemen suportif

hanya untuk pengobatan spesifik untuk menetralkan racun tetanus - tetanospasmin

& tetanolysin. Human Tetanus Immunoglobulin (HTIg) adalah molekul besar dan

tidak dapat melewati sawar darah otak. Pengenalan terapi intratekal sangat

menurunkan angka kematian dalam penyakit. Pemberian gabungan intramuskular

dan intratekal HTIg harus menetralkan racun tetanus dalam sirkulasi dan sistem

saraf pusat secara bersamaan. Penelitian ini dilakukan untuk mendeteksi efek

menguntungkan dari penambahan HTIg intramuskular ke terapi intratekal.

Metode: 125 pasien tetanus diacak ke dua kelompok. Kelompok studi diberikan

intratekal plus HTIg intramuskular sementara kelompok kontrol diberikan HTIg

intratekal saja. Setiap kelompok dibagi menjadi tiga kelas sesuai dengan tingkat

keparahannya. Angka kematian dan tiga parameter pemulihan berurutan yaitu

durasi kejang, beralih ke terapi oral dan durasi rawat inap diukur.

Hasil: Tidak ada perbedaan signifikan dalam mortalitas yang ditemukan. Namun,

pada pasien yang bertahan hidup, penambahan HTIg intramuskular menyebabkan

manfaat 2,07, 2,67 & 2,31 hari pada tingkat ringan, sedang & berat masing-

masing dalam durasi kejang. Selanjutnya, menjadi mungkin untuk memulai terapi

oral 2,13, 1,6 & 1,8 hari sebelumnya di tetanus ringan, sedang & berat. Durasi

tinggal di rumah sakit berkurang 3,87 hari, 2,36 hari dan 3 hari pada tetanus

ringan, sedang dan berat masing-masing.

Kesimpulan: Meskipun penambahan HTIg intramuskular ke terapi intratekal pada

tetanus tidak memberi manfaat kelangsungan hidup, hal ini menyebabkan

pemulihan lebih cepat pada pasien yang bertahan hidup.

PENGANTAR

  

Catatan paling awal mengenai tetanus ada di Edwin Smith Surgical Papyurs, yang

seharusnya bertanggal 19th Century B.C. Hippocrates di 460 B.C.

menggambarkan prognosis buruk dari penyakit ini. Sushruta menamakan penyakit

itu sebagai 'dhanushtambha'. Dalam gambaran klinis, ia menggambarkan lockjaw

sebagai kelumpuhan tulang rahang dan opisthotonus sebagai 'bahirayamma'.

Charak mengamati bahwa itu disebabkan angin yang dipicu mengeringkan saraf

luar belakang dan tengkuk 'leher. Dia lebih lanjut mencatat bahwa baik penyakit

itu membunuh pasien atau menyebabkan kelainan bentuk. Dokter Yunani

Aretaeus di abad pertama A. menyebutkannya sebagai "Bencana yang tidak

manusiawi, pemandangan yang tidak pantas, tontonan yang menyakitkan bahkan

untuk disaksikan".

Sir Charles melaporkan kasus tetanus di London. Pollack dari Dalin melaporkan

kasus serupa. Bose memberikan gambaran komprehensif pertama tentang

penyakit ini. Nicoliers menghasilkan tetanus dengan menyuntikkan hewan dengan

tanah kebun. Deskripsi berikutnya dari bacillus yang diperoleh dari situs injeksi

  

dalam budaya murni oleh Kitasato. Ehelich memisahkan dua racun yang berbeda

dan berbeda - Tetanospasmin dan Tetanolysin. Marier dan Morax dan Meyer &

Ransom mengamati aksi sentral toksin. Tulloch mengamati berbagai tipe serologis

yang berbeda dari bacillus.

Hingga abad ke-19, pengobatan terutama didasarkan pada anestesi umum yang

mudah menguap. Para dokter mengandalkan terutama pada opium dan berbagai

metode aneh dalam upaya untuk menangkap penyakit. Petunjuk pertama

pendekatan terapi rasional datang dengan pengenalan efek melumpuhkan otot dari

persiapan curare mentah dari Amerika Selatan. Sir Benjamin Collins Brodie

menunjukkan bahwa pernafasan dan bellow buatan melestarikan kehidupan

hewan kuraris.1 Collen menggunakan opium dosis besar dan juga

merekomendasikan penggunaan laksatif. O'Beirne merawat 20 pasien tetanus

dengan tembakau, tabung karet elastis dan minyak puring. Dia mengklaim

berhasil dalam 11 dari mereka. Von Bellin dan Kitasato berhasil imunisasi

terhadap tetanus. Ramon memperkenalkan tetanus toxoid 'anatoxine tétanique'

sebagai alat profilaksis untuk mencegah penyakit tetanus pada hewan peliharaan

(dengan P. Descombey) dan pada manusia. (dengan Ch. Zoeller) .

Clostridium tetani adalah gram positif, anaerobik, spora membentuk bacillus yang

menghasilkan racun yang menghancurkan, kedua setelah botulinum dalam

toksisitas. Dua racun penting yang dihasilkan oleh Cl. Tetani adalah

tetanospasmin dan tetanolysin. Tetanospasmin menargetkan saraf somatik dan

menyebabkan ketegangan otot dan spasme dengan menghalangi pelepasan

neurotransmiter penghambatan glisin dan asam gamma aminobutyric. Tetanolysin

juga menghambat mekanisme pengontrol saraf otonom, menghasilkan sistem

kardiovaskular labil, fungsi pernapasan yang tidak dapat diprediksi, berkeringat,

hiperpireksia dan gejala lain disfungsi otonom.

Racun yang dilepaskan oleh basil yang matang, diambil oleh sirkulasi limfatik dan

vaskular dan didistribusikan ke endplate dari semua saraf. Hal ini menghasilkan

serpihan serotonin secara simultan oleh semua saraf, yang kemudian mengarahkan

mereka secara sentripetal ke sistem saraf pusat. Tingkat penularan paling cepat di

sepanjang sensorik dan paling lambat di sepanjang neuron adrenergik, tetapi

kuantitas terbesar dilakukan oleh neuron motorik. Saraf terpendek adalah yang

pertama untuk mengeluarkan racun yang menimbulkan gejala awal yang normal

dari kekakuan punggung dan leher serta distorsi wajah. Ketika racun dikirim ke

sumsum tulang belakang oleh saraf yang lebih panjang, saraf motorik berurutan

secara berurutan sesuai dengan panjangnya sampai semua otot menjadi tidak

memiliki kendali atau kontrak sistem saraf pusat (SSP) atau mengalami kejang.

Disfungsi otonom menjadi semakin jelas ketika tingkat intoksikasi CNS

meningkat. Tetanus lokal adalah pengecualian dari penyebaran normal racun. Ini

hasil dari keracunan tunggal ujung saraf di tempat infeksi.

Tingkat keparahan tanda dan gejala secara langsung berkaitan dengan konsentrasi

toksin yang dibuang ke dalam aliran darah dan ditularkan oleh saraf ke sumsum

tulang belakang. Oleh karena itu penting untuk menetralisir racun dalam sirkulasi

sebelum mereka diambil oleh saraf, dan sama pentingnya untuk menetralkan

racun dalam cairan serebrospinal (CSF) sebelum mereka diperbaiki ke neuron.

Penghapusan racun dalam sirkulasi masih menyisakan racun yang mengalir di

sepanjang saraf. Setelah racun menjadi tetap, itu tidak bisa copot. Efeknya hanya

  

Penatalaksanaan konservatif tetanus terdiri dari perawatan yang baik, menjaga

pasien dalam lingkungan yang tenang, antibiotik untuk melawan infeksi, obat

penenang dan relaksan otot. Penatalaksanaan spesifik tetanus adalah menetralisir

racun tak terikat dengan memberikan antitoksin bersama dengan dukungan

kehidupan.

Antitoksin pertama yang digunakan adalah Antitetanus Serum (ATS) yang berasal

dari serum kuda. Karena reaksi anafilaksis parah yang dihasilkannya, ia

digantikan oleh Human Tetanus Immunoglobulin (HTIg) yang terbuat dari sera

manusia. Tetanus Immunoglobulin awalnya diberikan oleh rute intramuskular.

Dipostulasikan bahwa menjadi molekul besar, sebagian besar Tetanus

Immunoglobulin tidak dapat melewati sawar darah otak dan menetralkan racun

dalam sistem saraf pusat.

Ildrim adalah orang pertama yang mengamati keunggulan ATS intratekal lebih

ATS.5 intramuskular Tapi pada tahun 1979, Sedaghatian mengamati bahwa angka

kematian dan lamanya tinggal di rumah sakit tidak berbeda secara signifikan

ketika terapi intratekal diberikan dibandingkan dengan therapy.6 intramuskular

Vakil tidak menemukan signifikan perbedaan antara intratekal dan Opposite

pandangan groups.7 intravena keluar dalam studi Bhandari yang menunjukkan

bahwa intratekal terapi mengakibatkan kematian lebih tinggi daripada terapi

intramuskular sementara Mongi menunjukkan bahwa terapi intratekal lebih

unggul intramuskular dalam pengobatan tetanus.8,9 neonatal Menon juga

mengamati superioritas perawatan intratekal.10

Pada tahun 2004, Miranda-Filho dan rekan membandingkan kemanjuran HTIg

intramuscular (3.000 IU) ditambah HTIg intratekal (1.000 IU) dengan HTIg

intramuskular saja dan tidak menemukan perbedaan yang signifikan dalam

mortality.11 Tapi perbaikan yang signifikan diamati pada kelompok perlakuan

sehubungan kejang dan durasi tinggal di rumah sakit. Ahmad dan rekan

menemukan manfaat kematian yang signifikan dan tinggal di rumah sakit yang

lebih pendek ketika HTIg intratekal diberikan untuk tetanus neonatal.

Dalam meta-analisis pertama uji terapi intratekal vs intramuskular yang dilakukan

oleh Abrutyn, tidak ada manfaat seroterapi intratekal yang ditemukan.13 Namun

tidak semua uji coba dalam meta-analisis diacak. Sebuah meta-analisis dari uji

coba terkontrol secara acak yang dilakukan oleh Kabura dkk menemukan manfaat

signifikan menggunakan pengobatan intratekal dibandingkan dengan terapi

intramuskular. Meta-analisis juga menemukan manfaat signifikan menggunakan

penggunaan pengobatan intratekal dosis tinggi (> 250 IU). Dosis maksimum

perawatan intratekal adalah 1500 IU.

Pendapat saat ini adalah bahwa perawatan intratekal lebih efektif daripada

perawatan intramuskular dalam penatalaksanaan tetanus. Terlepas dari intratekal

vs rute intramuskular, rute intratekal telah dibandingkan dengan rute intravena dan

intratekal ditambah rute intramuskular telah dibandingkan dengan rute

intramuskular. Namun, belum ada studi sampai tanggal yang mengeksplorasi

kemungkinan efek menguntungkan menambahkan dosis intramuskular ke terapi

intratekal. Penelitian ini dilakukan untuk mengukur apakah ada efek

menguntungkan dalam bentuk penurunan mortalitas atau pemulihan lebih cepat

terjadi pada penambahan terapi intramuskular HTIg ke terapi intratekal.

Dipostulasikan bahwa sementara rute intratekal menetralkan racun dalam CSF,

  

terapi intramuskular harus memiliki efek yang menguntungkan aditif. Parameter

pemulihan yang digunakan dalam uji coba sebelumnya yaitu 'durasi kejang' dan

'durasi masa inap di rumah sakit' dibandingkan dalam penelitian ini. Selain ini,

'beralih ke terapi oral' juga digunakan sebagai parameter pemulihan untuk pertama

kalinya dalam studi apa pun.

METODE

  

125 pasien tetanus dilibatkan dalam penelitian ini. Informed consent diambil dari

pasien. Mereka yang setuju untuk berpartisipasi dalam penelitian diacak ke dua

kelompok. 65 kasus dialokasikan untuk kelompok studi dan 60 kasus dialokasikan

untuk kelompok kontrol. Kelompok studi pasien diberikan intratekal ditambah

HTIg intramuskular. Ini dibandingkan dengan kelompok kontrol yang terdiri dari

60 pasien yang diberikan HTIg intratekal saja. Perawatan pendukung serupa pada

kedua kelompok.

Pada pasien kelompok studi, pungsi lumbal dilakukan dengan aseptic care yang

ketat dan 2 ml CSF dikeluarkan. Kemudian HTIg disuntikkan secara intratekal.

Situs tusukan disegel dengan benar. Bersamaan HTIg disuntikkan intramuskular.

Dosis HTIg di IU adalah sebagai berikut: 2-5 tahun - intratekal 500 ditambah

intramuskular 500, 5-10 tahun - intratekal 1000 ditambah intramuscular 750, > 10

tahun - intratekal 1500 ditambah intramuskular 1000. Pada kelompok kontrol,

hanya pemberian intratekal HTIg seperti yang disebutkan di atas dilakukan.

Semua pasien diberi rejimen rutin suntik Penicillin, Diazepam, Methocarbamol,

Chlorpromazine, dll. Pasien di bawah 2 tahun atau di atas 70 tahun dan mereka

yang meninggal dalam 12 jam setelah masuk dikeluarkan dari penelitian.

Lima kriteria digunakan dalam menilai tingkat keparahan penyakit. Kriteria (C) -

1: Lockjaw, C-2: Spasme, C-3: Masa inkubasi 7 hari atau kurang, C-4: Periode

onset kejang 48 jam atau kurang, C-5: Demam didefinisikan sebagai aksila suhu

99 ° F atau suhu rektal 100 ° F saat masuk atau dalam 24 jam setelah masuk. Grading ini telah dimodifikasi dari kriteria yang dibuat oleh Patel dan Joag.15 Penilaian dilakukan sebagai berikut:

• • Ringan: Hanya satu atau dua dari lima kriteria, umumnya C-1 dan / atau C-2.

  Sesekali demam (C-5) dengan C-1 atau C-2.

• • Sedang: Terdiri dari tiga dari lima kriteria, yaitu C-1 + C-2 dan salah satu dari

  tiga kriteria lainnya.
• Parah: Terdiri dari setidaknya empat dari lima kriteria.

  Sebuah studi perbandingan antara masing-masing kelas yang sesuai dari kedua

  kelompok dilakukan mengenai tingkat kelangsungan hidup, durasi persistensi

  kejang, beralih ke terapi oral, durasi rawat inap dan efek samping.

  Fisher Exact Test digunakan untuk perbandingan mortalitas. Data variabel kontinu

  dibandingkan dengan t-test independen dan dilaporkan sebagai rata-rata ± standar

  deviasi (SD). p <0,05 dianggap signifikan.

HASIL

  

Angka kematiannya nol dalam tetanus ringan di kedua kelompok. Tidak ada

perbedaan signifikan dalam mortalitas yang ditemukan karena penambahan HTIg

intramuskular pada tetanus sedang dan berat (Tabel 1). Secara keseluruhan

  

signifikan dari mortalitas standar untuk tingkat keparahan kelompok kontrol yang

14,88% (Tabel 1a).

Penambahan intramuskular HTIg memiliki efek yang signifikan pada durasi

kejang pada tetanus ringan, sedang dan berat (Tabel 2). Spasme bertahan hanya

rata-rata 0,33 hari pada tetanus ringan dalam kelompok studi dibandingkan

dengan 2,4 hari pada kelompok kontrol. Pada tetanus moderat & berat,

perbedaannya sangat sangat signifikan. Kejang hanya berlangsung rata-rata 1 hari