Post-neonatal Tetanus in a PICU of a Developing Economy: Intensive Care Needs, Outcome and Predictors of Mortality

Post-neonatal Tetanus in a PICU of a Developing Economy: Intensive Care Needs, Outcome and... ABSTRACT Objectives To evaluate pediatric intensive care unit (PICU) needs, outcome and predictors of mortality in post-neonatal tetanus. Materials and methods Review of 30 consecutive post-neonatal tetanus cases aged 1 months to 12 years admitted to a PICU in north India over a period of 10 years (January 2006 to December 2015). Results Chronic suppurative otitis media was the commonest portal of entry. All received tetanus toxoid, human tetanus immunoglobulin (HTIG) and appropriate antibiotics; 7 (23.3%) received intrathecal HTIG. Common complications were respiratory failure, rhabdomyolysis, autonomic dysfunction, acute kidney injury and healthcare-associated infections. PICU needs were as follows: ventilation; benzodiazepine, morphine and magnesium sulfate infusion; neuromuscular blockers, inotropes, tracheostomy and renal replacement therapy. Mortality rate was 40%; severity Grade IIIb, autonomic dysfunction, use of vasoactive drugs and those who did not receive intrathecal HTIG were significantly associated with mortality. Conclusion Post-neonatal tetanus is associated with high mortality, and PICU needs include management of spasms, autonomic dysfunction and complications and cardiorespiratory support. post-neonatal tetanus, human tetanus immunoglobulin, spasms, autonomic dysfunction INTRODUCTION Tetanus is a vaccine-preventable disease acquired through environmental exposure to spores of Clostridium tetani. Effective immunization has reduced the incidence of tetanus significantly in the developed world. On the contrary, it remains a major public health problem associated with significant morbidity and mortality in developing countries [1, 2]. Management in pediatric intensive care unit (PICU) is of paramount importance for control of spasms and muscle rigidity and for management of various complications including respiratory failure, acute kidney injury (AKI), autonomic dysfunction and healthcare-associated infections (HCAIs). Short incubation period (<7 days), short onset time (<3 days), autonomic dysfunction and cephalic tetanus are reported predictors of mortality [3, 4]. Human tetanus immunoglobulin (HTIG) is one of the pillars in management and combined use of intramuscular and intrathecal HTIG is associated with improved outcome [5–7]. Despite being rampant in developing economies, there is paucity of data on post-neonatal tetanus cases treated in PICU of resource-limited settings, especially India [1, 7–15]. Therefore, this study was planned to analyze clinical profile, treatment, complications, intensive care needs, outcome and predictors of mortality in children with post-neonatal tetanus admitted to a PICU. MATERIALS AND METHODS This was a retrospective study conducted in PICU of a tertiary care teaching hospital in North India. All children, 1 month to 12 years, admitted to PICU from January 2006 to December 2015 with diagnosis of post-neonatal tetanus were included. Our PICU is a medical ICU with 15 beds having facilities for ventilation and invasive and noninvasive monitoring. In recent years, total PICU admissions have been around 800–900 cases/year. The nurse to patient ratio is 1:1 for ventilated patients and 1:2 for non-ventilated patients. The diagnosis of post-neonatal tetanus was clinical (i.e. presence of trismus, risus sardonicus and/or provoked or unprovoked spasms) [1]. All cases were treated according to management protocol for tetanus used in our PICU [1]. Ethical clearance was sought from the institute ethics committee. Data were retrieved from case records and entered on a structured proforma. Information on demographics, portal of entry, vaccination status, type and Ablett’s severity grade, incubation period, period of onset, duration of illness, clinical features, treatment, complications, duration of PICU stay, outcome and follow up were recorded. Incubation period was defined as interval between acute injury and first symptom, while period of onset was taken as interval between first symptom and first spasm [1, 13]. Details regarding wound debridement and antibiotics, removal of unbound toxin (HTIG, intramuscular with/without intrathecal), control of spasms (benzodiazepines and muscle relaxants), control of autonomic dysfunction (morphine and magnesium sulfate) and supportive care (ventilation, inotropes, tracheostomy and peritoneal dialysis) were noted. Complications related to tetanus and PICU stay were included. Outcome (survival or death), length of PICU stay, status at discharge and follow up were also noted. STATISTICAL ANALYSIS Data entry and statistical analysis were performed on Microsoft Excel 2010 (Microsoft excel, Redmond, WA) and SPSS software version 21 (IBM SPSS, Armonk, NY). Descriptive statistics (mean, SD, median, range and percentages) were used for baseline variables. Survivors and non-survivors were compared using Chi-square test or Fisher exact test for dichotomous outcomes and Student t-test for continuous variables. Univariate and multivariate analyses were done for predictors of mortality. p < 0.05 was taken as significant. RESULTS A total of 30 patients with post-neonatal tetanus were identified of 6176 PICU admissions during study period (0.48% of total admission) (Fig. 1). There were 23 (76.7%) boys with a mean (±SD) age of 7.2 (±2.9) years. More than half (17, 56.7%) were completely unimmunized (Table 1). Most common portal of entry was chronic suppurative otitis media (CSOM) (n = 16, 53.3%) followed by acute injury (n = 10, 33.3%). Incubation period in cases with injury was 7 (±2.2) days. Duration of illness before presentation and period of onset were 5.6 (±3.5) and 3.8 (±2.7) days, respectively. All patients had generalized spasms at the time of admission. Other features noted are shown in Table 1. All patients had generalized tetanus with Ablett’s severity Grade IIIa (36.7%) and Grade IIIb (63.3%) (Table 1). Table 1 Clinical characteristics of cases with tetanus admitted to PICU Characteristics  Number of cases (n = 30)  Age in years, mean (SD)  7.2 (2.9)  Male gender, n (%)  23 (76.7)  PRISM III, median (IQR)  15.4 (10-32)  Vaccination status     Complete vaccination  0   Not vaccinated, n (%)  17 (56.7)   Partial vaccination, n (%)  8 (26.7)   Status not known, n (%)  5 (16.7)  Portal of entry     CSOM, n (%)  16 (53.3)   Duration of CSOM in months, mean (SD)  15.32 (11.3)   Injury, n (%)  10 (33.3)   Lower limbs, n (%)  6 (20)   Head and neck area, n (%)  2 (6.7)   Upper limb, n (%)  1 (3.3)   No injury, n (%)  4 (13.3)  Incubation period in days for cases with injury, mean (SD)  7 (2.2)  Duration of illness in days, mean (SD)  5.6 (3.5)  Period of onset in days, mean (SD)  3.8 (2.7)  Clinical features     Generalized spasms, n (%)  30 (100)   Trismus, n (%)  28 (93.3)   Jaw pain, n (%)  23 (76.7)   Risus sardonicus, n (%)  21 (70)   Opisthotonus, n (%)  20 (66.7)   Cervical rigidity, n (%)  16 (53.3)   Dysphagia, n (%)  14 (46.7)   Body ache, n (%)  6 (20)   Fever, n (%)  4 (13.3)   Dysarthria, n (%)  3 (10)   Laryngospasms, n (%)  2 (6.6)  Type of tetanus     Generalized, n (%)  30 (100)   Cervical, n (%)  0   Localized, n (%)  0  Severity of tetanus     Grade IIIa, n (%)  11 (36.7)   Grade IIIb, n (%)  19 (63.3)  Characteristics  Number of cases (n = 30)  Age in years, mean (SD)  7.2 (2.9)  Male gender, n (%)  23 (76.7)  PRISM III, median (IQR)  15.4 (10-32)  Vaccination status     Complete vaccination  0   Not vaccinated, n (%)  17 (56.7)   Partial vaccination, n (%)  8 (26.7)   Status not known, n (%)  5 (16.7)  Portal of entry     CSOM, n (%)  16 (53.3)   Duration of CSOM in months, mean (SD)  15.32 (11.3)   Injury, n (%)  10 (33.3)   Lower limbs, n (%)  6 (20)   Head and neck area, n (%)  2 (6.7)   Upper limb, n (%)  1 (3.3)   No injury, n (%)  4 (13.3)  Incubation period in days for cases with injury, mean (SD)  7 (2.2)  Duration of illness in days, mean (SD)  5.6 (3.5)  Period of onset in days, mean (SD)  3.8 (2.7)  Clinical features     Generalized spasms, n (%)  30 (100)   Trismus, n (%)  28 (93.3)   Jaw pain, n (%)  23 (76.7)   Risus sardonicus, n (%)  21 (70)   Opisthotonus, n (%)  20 (66.7)   Cervical rigidity, n (%)  16 (53.3)   Dysphagia, n (%)  14 (46.7)   Body ache, n (%)  6 (20)   Fever, n (%)  4 (13.3)   Dysarthria, n (%)  3 (10)   Laryngospasms, n (%)  2 (6.6)  Type of tetanus     Generalized, n (%)  30 (100)   Cervical, n (%)  0   Localized, n (%)  0  Severity of tetanus     Grade IIIa, n (%)  11 (36.7)   Grade IIIb, n (%)  19 (63.3)  Fig. 1. View largeDownload slide Study flow diagram. Fig. 1. View largeDownload slide Study flow diagram. Wound debridement was required in 9 of 10 (90%) cases with injury. All cases received tetanus toxoid and intramuscular HTIG (500 U). We started using intrathecal HTIG from 2012, and seven (23.3%) cases received it in doses of 1000 U. All patients were treated with appropriate antibiotics [crystalline penicillin in 23 (76.7%) or metronidazole in 7 (23.3%)] (Table 2). Table 2 Treatment details Treatment details  Number of cases (n = 30)  Wound debridement among those with injury, n (%)  9 (30)  Tetanus toxoid, n (%)  30 (100)  HTIG, n (%)  30 (100)  Intrathecal HTIG, n (%)  7 (23.3)  Antibiotic     Crystalline Penicillin, n (%)  23 (76.7)   Metronidazole, n (%)  7 (23.3)   Midazolam, n (%)  6 (20)   Duration in days, mean (SD)  2.6 (1.3)   Diazepam, n (%)  30 (100)   Duration in days, mean (SD)  20.7 (10.5)   Morphine, n (%)  29 (96.7)   Duration in days, mean (SD)  15.59 (9.1)   Magnesium sulfate, n (%)  26 (86.7)   Duration in days, mean (SD)  14.84 (9.2)   Muscle relaxant, n (%)  21 (70)   Duration in days, mean (SD)  6.84 (2.4)   Intubation, n (%)  30 (100)   Ventilation, n (%)  30 (100)   Duration in days, mean (SD)  16 (6.2)   Tracheostomy, n (%)  12 (40)   On day of PICU stay, mean (SD)  12.3 (5.1)   Inotropes, n (%)  20 (66.7)   Duration in days, mean (SD)  3.87 (2.1)   Peritoneal dialysis, n (%)  10 (33.3)  Treatment details  Number of cases (n = 30)  Wound debridement among those with injury, n (%)  9 (30)  Tetanus toxoid, n (%)  30 (100)  HTIG, n (%)  30 (100)  Intrathecal HTIG, n (%)  7 (23.3)  Antibiotic     Crystalline Penicillin, n (%)  23 (76.7)   Metronidazole, n (%)  7 (23.3)   Midazolam, n (%)  6 (20)   Duration in days, mean (SD)  2.6 (1.3)   Diazepam, n (%)  30 (100)   Duration in days, mean (SD)  20.7 (10.5)   Morphine, n (%)  29 (96.7)   Duration in days, mean (SD)  15.59 (9.1)   Magnesium sulfate, n (%)  26 (86.7)   Duration in days, mean (SD)  14.84 (9.2)   Muscle relaxant, n (%)  21 (70)   Duration in days, mean (SD)  6.84 (2.4)   Intubation, n (%)  30 (100)   Ventilation, n (%)  30 (100)   Duration in days, mean (SD)  16 (6.2)   Tracheostomy, n (%)  12 (40)   On day of PICU stay, mean (SD)  12.3 (5.1)   Inotropes, n (%)  20 (66.7)   Duration in days, mean (SD)  3.87 (2.1)   Peritoneal dialysis, n (%)  10 (33.3)  All patients initially received intravenous diazepam infusion (5–40 mg/kg/day) for spasm control followed by oral diazepam for duration of 20.7 (±10.5) days once spasms were controlled. Morphine and magnesium sulfate infusions were used for control of autonomic dysfunction: the former was used in 29 (96.7%) cases for 15.6 (±9.1) days in doses of 20–50 µg/kg/h and the latter in 26 (86.7%) cases for 14.8 (±9.2) days in doses of 100–200 mg/kg/day. For spasms refractory to above therapy, neuromuscular blocking agents were used (n = 21, 70%) for 6.8 (±2.4) days. All children were ventilated for 16 (±6.2) days. Tracheostomy was done in 12 (40%) at 12.3 (±5.1) days of admission. Vasoactive drugs were used in 20 (66.7%) cases (Table 2). All cases had one or other complication related to primary disease or therapy (Table 3). Most common was respiratory failure followed by rhabdomyolysis, AKI, autonomic dysfunction and HCAIs (Table 3). Of three cases with cardiac arrest, two survived. Table 3 Complications related to tetanus and PICU stay Complications  Number of cases (n = 30)  Number of patients with complications, n (%)  30 (100)  Rhabdomyolysis, n (%)  23 (76.7)  AKI, n (%)  19 (63.3)  Respiratory complications  30 (100)   Respiratory failure, n (%)  28 (93.3)   Laryngospasm, n (%)  2 (6.7)   Aspiration pneumonia, n (%)  1 (3.3)  Autonomic dysfunction, n (%)  19 (63.3)  On day of admission, mean (SD)  6.2 (3.7)   Bradycardia, n (%)  8 (26.7)   Hypotension, n (%)  7 (23.3)   Hypertension, n (%)  6 (20)   Diaphoresis, n (%)  5 (16.7)   Cardiac arrest, n (%)  3 (10)  Healthcare-associated infections  14 (46.7)   Ventilator-associated pneumonia, n (%)  9 (30)   Blood stream infection, n (%)  6 (20)   Urinary tract infection, n (%)  5 (16.7)  Paralytic ileus, n (%)  5 (16.7)  Pneumothorax, n (%)  3 (10)  Bed sores, n (%)  2 (6.7)  Deep venous thrombosis, n (%)  1 (3.3)  Complications  Number of cases (n = 30)  Number of patients with complications, n (%)  30 (100)  Rhabdomyolysis, n (%)  23 (76.7)  AKI, n (%)  19 (63.3)  Respiratory complications  30 (100)   Respiratory failure, n (%)  28 (93.3)   Laryngospasm, n (%)  2 (6.7)   Aspiration pneumonia, n (%)  1 (3.3)  Autonomic dysfunction, n (%)  19 (63.3)  On day of admission, mean (SD)  6.2 (3.7)   Bradycardia, n (%)  8 (26.7)   Hypotension, n (%)  7 (23.3)   Hypertension, n (%)  6 (20)   Diaphoresis, n (%)  5 (16.7)   Cardiac arrest, n (%)  3 (10)  Healthcare-associated infections  14 (46.7)   Ventilator-associated pneumonia, n (%)  9 (30)   Blood stream infection, n (%)  6 (20)   Urinary tract infection, n (%)  5 (16.7)  Paralytic ileus, n (%)  5 (16.7)  Pneumothorax, n (%)  3 (10)  Bed sores, n (%)  2 (6.7)  Deep venous thrombosis, n (%)  1 (3.3)  Twelve (40%) children died. The duration of PICU stay among survivors and non-survivors was 22.2 (±10.3) and 7.7 (±5.9) days, respectively. We were able to follow up 14 (46.7%) survivors for a duration of 5.6 (±3.8) months of which 13 were well and 1 had post-cardiac arrest neurological sequelae at the time of last follow up (Table 4). Univariate and multivariate logistic regression analyses revealed that severity Grade IIIb, autonomic dysfunction, those who did not receive intrathecal HTIG and requirement of vasoactive drugs were significantly associated with mortality (Table 5). Table 4 Outcome and follow up details Outcome and follow up details  Number of cases (n = 30)  Outcome     Survived, n (%)  18 (60)   Died, n (%)  12 (40)   Duration of PICU stay among survivors in days, mean (SD)  22.2 (10.3)   Duration of PICU stay among non-survivors in days, mean (SD)  7.8 (5.9)  Status at discharge     Well, n (%)  16 (53.3)   Discharged with sequelae, n (%)  2 (6.7)   Number of cases followed up, n (%)  14 (46.7)   Duration in months after discharge from PICU, mean (SD)  5.62 (3.8)  Status at follow up     Well, n (%)  13 (43.3)   With sequelae, n (%)  1 (3.3)  Outcome and follow up details  Number of cases (n = 30)  Outcome     Survived, n (%)  18 (60)   Died, n (%)  12 (40)   Duration of PICU stay among survivors in days, mean (SD)  22.2 (10.3)   Duration of PICU stay among non-survivors in days, mean (SD)  7.8 (5.9)  Status at discharge     Well, n (%)  16 (53.3)   Discharged with sequelae, n (%)  2 (6.7)   Number of cases followed up, n (%)  14 (46.7)   Duration in months after discharge from PICU, mean (SD)  5.62 (3.8)  Status at follow up     Well, n (%)  13 (43.3)   With sequelae, n (%)  1 (3.3)  Table 5 The predictors of mortality according to univariate and multivariate logistic regression analyses Predictor variables  Survivors (n = 18)  Non-survivors (n = 12)  Univariate analysis  Multivariate analysis  Age      0.052    ≤7 years, n (%)  11 (61.1)  3 (25)      >7 years, n (%)  7 (38.9)  9 (75)      Incubation period in days, mean (SD)  7.14 (1.57)  6.5 (4.9)  0.74    Period of onset in days, mean (SD)  4.27 (3.67)  3.08 (2.23)  0.33    Duration of illness in days, mean (SD)  6.38 (3.87)  4.58 (2.67)  0.18    ≤7 days, n (%)  12 (66.7)  8 (66.7)  0.91    >7 days, n (%)  6 (29.4)  4 (33.3)      Portal of entry      0.27     Head and neck, n (%)  11 (64.7)  6 (50)       Others, n (%)  6 (33.3)  6 (50)      Severity of tetanus      0.008  0.01   Grade IIIa, n (%)  10 (55.6)  1 (8.3)       Grade IIIb, n (%)  8 (44.4)  11 (91.7)      Intrathecal HTIG      0.013  0.004   Yes, n (%)  7 (38.9)  0 (0)       No, n (%)  11 (61.1)  12 (100)      Use of inotropes      0.001  0.002   Yes, n (%)  8 (44.4)  12 (100)       No, n (%)  10 (55.6)  0 (0)      Autonomic dysfunction      0.008  0.02   Yes, n (%)  8 (44.4)  11 (91.7)       No, n (%)  10 (55.6)  1 (8.3)      Rhabdomyolysis      0.19     Yes, n (%)  13 (72.2)  11 (91.7)       No, n (%)  5 (27.8)  1 (8.3)      AKI      0.06     Yes, n (%)  9 (50)  10 (83.3)       No, n (%)  9 (50)  2 (16.7)      HCAIs      0.76     Yes, n (%)  8 (44.4)  6 (50)       No, n (%)  10 (55.6)  6 (50)      Ventilator associated pneumonia      0.25     Yes, n (%)  4 (22.2)  5 (41.7)       No, n (%)  14 (77.8)  7 (58.3)      Predictor variables  Survivors (n = 18)  Non-survivors (n = 12)  Univariate analysis  Multivariate analysis  Age      0.052    ≤7 years, n (%)  11 (61.1)  3 (25)      >7 years, n (%)  7 (38.9)  9 (75)      Incubation period in days, mean (SD)  7.14 (1.57)  6.5 (4.9)  0.74    Period of onset in days, mean (SD)  4.27 (3.67)  3.08 (2.23)  0.33    Duration of illness in days, mean (SD)  6.38 (3.87)  4.58 (2.67)  0.18    ≤7 days, n (%)  12 (66.7)  8 (66.7)  0.91    >7 days, n (%)  6 (29.4)  4 (33.3)      Portal of entry      0.27     Head and neck, n (%)  11 (64.7)  6 (50)       Others, n (%)  6 (33.3)  6 (50)      Severity of tetanus      0.008  0.01   Grade IIIa, n (%)  10 (55.6)  1 (8.3)       Grade IIIb, n (%)  8 (44.4)  11 (91.7)      Intrathecal HTIG      0.013  0.004   Yes, n (%)  7 (38.9)  0 (0)       No, n (%)  11 (61.1)  12 (100)      Use of inotropes      0.001  0.002   Yes, n (%)  8 (44.4)  12 (100)       No, n (%)  10 (55.6)  0 (0)      Autonomic dysfunction      0.008  0.02   Yes, n (%)  8 (44.4)  11 (91.7)       No, n (%)  10 (55.6)  1 (8.3)      Rhabdomyolysis      0.19     Yes, n (%)  13 (72.2)  11 (91.7)       No, n (%)  5 (27.8)  1 (8.3)      AKI      0.06     Yes, n (%)  9 (50)  10 (83.3)       No, n (%)  9 (50)  2 (16.7)      HCAIs      0.76     Yes, n (%)  8 (44.4)  6 (50)       No, n (%)  10 (55.6)  6 (50)      Ventilator associated pneumonia      0.25     Yes, n (%)  4 (22.2)  5 (41.7)       No, n (%)  14 (77.8)  7 (58.3)      Note: Bold characters show significant p-value. DISCUSSION The present study recorded a 0.48% prevalence of post-neonatal tetanus among children admitted to PICU of a tertiary care teaching hospital in North India over a period of 10 years. Generalized spasms, trismus, jaw pain, risus sardonicus, opisthotonus, cervical rigidity, dysphagia, body ache, fever, dysarthria were common clinical features in our patients similar to that noted by other authors [1, 7–15]. All patients had generalized tetanus. None of the cases were completely immunized, a finding documented in other studies too from developing counties [1, 7–15]. Portal of entry was identified in 86.7% cases, the most common being CSOM followed by acute injury. There was no identifiable portal of entry in 13.3% cases. This pattern is also similar to other studies involving children with post-neonatal tetanus [7, 8, 10, 14, 16]. Mishra et al. [14] in a retrospective review of 77 children with post-neonatal tetanus identified that otogenic route of infection (58.4%) and trauma (23.3%) were most common portals of entry. Narang et al. [7] studied 70 children with post-neonatal tetanus, and found that 64 (91.4%) had an identifiable portal of entry: ear discharge in 60% (42 of 70) and acute wound in 31.4% (22 of 70). Other studies identified lower limb injury as the commonest portal of entry [15–17]. All cases received appropriate antibiotics, tetanus toxoid and intramuscular HTIG and few received intrathecal HTIG (n = 7, 23.3%). All cases required diazepam (intravenous infusion followed by oral, for 3 weeks) and morphine and magnesium sulfate infusion (for 2 weeks each). Similarly, all cases also required ventilation for around 2–3 weeks. The duration of requirement of intensive care and supportive therapy corresponds to natural history of tetanus where active spasms are known to last for 2–3 weeks [1]. The common complications noted were respiratory failure, rhabdomyolysis, AKI, autonomic dysfunction (in second week of illness) and HCAIs. Rhabdomyolysis in tetanus is due to generalized muscle spasms. Myoglobinuria, hypotension, diazepam and sepsis can lead to AKI [9, 15]. Respiratory complications are due to spasms, laryngospasm, aspiration and heavy sedation. Autonomic imbalances (bradycardia/tachycardia, hypotension/hypertension and sudden cardiac arrest), HCAIs, paralytic ileus, decubitus ulcer and constipation have been reported in various studies [1, 3, 9–11] as noted in index study. We however documented a higher proportion of cases having autonomic dysfunction (63%) unlike an adult study where it was present in only one-third of patients (3). The mortality rate (40%) in the current study was within the range reported by other studies from developing countries (4.1–78.9%) [10–15]. Ours being a tertiary referral center catering to a wide region, the sickest cases are referred to us, thus explaining the high mortality seen in our cohort. Deaths occurred at the end of the first week of PICU stay (7.8 ± 5.9 days); immediate cause of death being refractory shock due to sepsis and autonomic dysfunction (n = 6), sudden cardiac arrest due to autonomic dysfunction (n = 3), pneumothorax (n = 2) and multifactorial (n = 1). We found that the non-survivors had more severe illness (Grade IIIb), autonomic dysfunction, had not received intrathecal HTIG and required vasoactive drugs. Aggarwal et al. [12] in a study involving 57 children documented that autonomic dysfunction was seen in 17.5% cases and was significantly associated with mortality (p = 0.025). Wasay et al. [3] studied 96 adults with tetanus and documented that autonomic dysfunction even in mild or moderate tetanus, irrespective of the need for mechanical ventilation, predicted poor outcome (59). Age, incubation period, duration of illness, period of onset, site of injury, AKI or HCAIs did not have any association with mortality in our cohort unlike few studies in which shorter incubation and period of onset were associated with mortality [4, 12, 18]. We observed that use of intrathecal HTIG along with intramuscular HTIG was associated with good outcome. Our findings were similar to that of Narang et al. [7] who in their retrospective study of 70 post-neonatal tetanus, found that mortality was higher (25%, 7 of 28) in those who received intramuscular HTIG alone as compared with those who received both intramuscular and intrathecal HTIG (4.7%, 2 of 42) (p = 0.025). Other studies have also demonstrated the superiority of intrathecal and intramuscular administration of HTIG as compared with intramuscular route alone [5, 6]. Miranda-Filho et al. [5] from a Brazilin study involving 120 patients with tetanus demonstrated better clinical outcomes in the form of shortened duration of spasms, hospital stay and respiratory assistance in patients who received combined intrathecal and intramuscular HTIG when compared with intramuscular route alone. Kabura et al. [6] in a meta-analysis involving 12 trials (n= 942; 484 in intrathecal group and 458 in intramuscular group) demonstrated that intrathecal HTIG or equine tetanus antitoxin was superior to intramuscular in preventing mortality (Relative risk: 0.71, 95% confidence interval: 0.62, 0.81). Intrathecal therapy retained its superiority in both adults and neonates and also for high and low dose. Intrathecal HTIG binds faster to the toxins released by C. tetani in central nervous system and neutralizes it in a better way as compared with intramuscular HTIG [6]. Prolonged hospitalization (around 3 weeks) was similar to that reported in other studies [9, 12, 15]. Half of the survivors (53.3%) were discharged with good neurological status; only one had post-cardiac arrest neurological sequelae at the time of the last follow up. This study summarizes the demographic, clinical profile, treatment and complications of post-neonatal tetanus in PICU over a period of 10 years from a resource-limited set up where data are scarce despite the disease being a major public health problem. Use of intrathecal HTIG may be associated with better survival. Despite intensive care, the mortality continues to be high, thus reiterating the need for prevention with better immunization coverage. We were able to follow three-fourth (14 of 18) of the discharged patients for a period of 6 months, and the outcome was good. The study however suffers from all limitations of a retrospective study. CONCLUSION Tetanus is still a major public health problem in developing countries including India. Improving routine immunization coverage, prompt treatment of CSOM, appropriate wound management are paramount for prevention of tetanus. Management includes control of spasms, respiratory and hemodynamic support and treatment of autonomic dysfunction and complications. Mortality remains high despite PICU care. Combined use of intrathecal and intramuscular HTIG is superior to intramuscular HTIG alone in reducing mortality. References 1 Singhi S, Jain V, Subramanian C. Post-neonatal tetanus: issues in intensive care management. Indian J Pediatr  2001; 68: 267– 72. Google Scholar CrossRef Search ADS PubMed  2 Vandelaer J, Birmingham M, Gasse F, et al.   Tetanus in developing countries: an update on the Maternal and Neonatal Tetanus Elimination Initiative. Vaccine  2003; 21: 3442– 5. Google Scholar CrossRef Search ADS PubMed  3 Wasay M, Khealani BA, Talati N, et al.   Autonomic nervous system dysfunction predicts poor prognosis in patients with mild to moderate tetanus. BMC Neurol  2005; 5: 2. Google Scholar CrossRef Search ADS PubMed  4 Bhatia R, Prabhakar S, Grover VK. Tetanus. Neurol India  2002; 50: 398– 407. Google Scholar PubMed  5 Miranda-Filho Dde B, Ximenes RA, Barone AA, et al.   Randomised controlled trial of tetanus treatment with antitetanus immunoglobulin by the intrathecal or intramuscular route. BMJ  2004; 328: 615. Google Scholar CrossRef Search ADS PubMed  6 Kabura L, Ilibagiza D, Menten J, et al.   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. Google Scholar CrossRef Search ADS PubMed  7 Narang M, Khurana A, Gomber S, et al.   Epidemiological trends of tetanus from East Delhi, India: a hospital-based study. J Infect Public Health  2014; 7: 121– 4. Google Scholar CrossRef Search ADS PubMed  8 Mondal T, Aneja S, Tyagi A, et al.   A study of childhood tetanus in post-neonatal age group in Delhi. Indian Pediatr  1994; 31: 1369– 72. Google Scholar PubMed  9 Tullu MS, Deshmukh CT, Kamat JR. Experience of pediatric tetanus cases from Mumbai. Indian Pediatr  2000; 37: 765– 71. Google Scholar PubMed  10 Geeta MG, Krishnakumar P, Mathews L. Intrathecal tetanus immunoglobulins in the management of tetanus. Indian J Pediatr  2007; 74: 43– 5. Google Scholar CrossRef Search ADS PubMed  11 Poudel P, Singh R, Raja S, et al.   Pediatric and neonatal tetanus: a hospital based study at eastern Nepal. Nepal Med Coll J  2008; 10: 170– 5. Google Scholar PubMed  12 Aggarwal M, Sood V, Aggarwal KC. Tetanus in pediatric patients–predictors affecting mortality and role of immunoglobulin. Indian Pediatr  2011; 48: 987– 8. Google Scholar PubMed  13 Oyedeji OA, Fadero F, Joel-Medewase V, et al.   Trends in neonatal and post-neonatal tetanus admissions at a Nigerian teaching hospital. J Infect Dev Ctries  2012; 6: 847– 53. Google Scholar CrossRef Search ADS PubMed  14 Mishra K, Basu S, Kumar D, et al.   Tetanus - still a scourge in the 21st century: a paediatric hospital-based study in India. Trop Doct  2012; 42: 157– 9. Google Scholar CrossRef Search ADS PubMed  15 Animasahun BA, Gbelee OH, Ogunlana AT, et al.   Profile and outcome of patients with post-neonatal tetanus in a tertiary centre in south west Nigeria: any remarkable reduction in the scourge?. Pan Afr Med J  2015; 21: 254. Google Scholar CrossRef Search ADS PubMed  16 Lau LG, Kong KO, Chew PH. A ten-year retrospective study of tetanus at a general hospital in Malaysia. Singapore Med J  2001; 42: 346– 50. Google Scholar PubMed  17 Onwuekwe IO, Onyedum CC, Nwabueze AC. Experience with tetanus in a tertiary hospital in south east Nigeria. Niger J Med  2008; 17: 50– 2. Google Scholar CrossRef Search ADS PubMed  18 Cook TM, Protheroe RT, Handel JM. Tetanus: a review of the literature. Br J Anaesth  2001; 87: 477– 87. Google Scholar CrossRef Search ADS PubMed  © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Tropical Pediatrics Oxford University Press

Post-neonatal Tetanus in a PICU of a Developing Economy: Intensive Care Needs, Outcome and Predictors of Mortality

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Oxford University Press
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© The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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0142-6338
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1465-3664
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10.1093/tropej/fmx020
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Abstract

ABSTRACT Objectives To evaluate pediatric intensive care unit (PICU) needs, outcome and predictors of mortality in post-neonatal tetanus. Materials and methods Review of 30 consecutive post-neonatal tetanus cases aged 1 months to 12 years admitted to a PICU in north India over a period of 10 years (January 2006 to December 2015). Results Chronic suppurative otitis media was the commonest portal of entry. All received tetanus toxoid, human tetanus immunoglobulin (HTIG) and appropriate antibiotics; 7 (23.3%) received intrathecal HTIG. Common complications were respiratory failure, rhabdomyolysis, autonomic dysfunction, acute kidney injury and healthcare-associated infections. PICU needs were as follows: ventilation; benzodiazepine, morphine and magnesium sulfate infusion; neuromuscular blockers, inotropes, tracheostomy and renal replacement therapy. Mortality rate was 40%; severity Grade IIIb, autonomic dysfunction, use of vasoactive drugs and those who did not receive intrathecal HTIG were significantly associated with mortality. Conclusion Post-neonatal tetanus is associated with high mortality, and PICU needs include management of spasms, autonomic dysfunction and complications and cardiorespiratory support. post-neonatal tetanus, human tetanus immunoglobulin, spasms, autonomic dysfunction INTRODUCTION Tetanus is a vaccine-preventable disease acquired through environmental exposure to spores of Clostridium tetani. Effective immunization has reduced the incidence of tetanus significantly in the developed world. On the contrary, it remains a major public health problem associated with significant morbidity and mortality in developing countries [1, 2]. Management in pediatric intensive care unit (PICU) is of paramount importance for control of spasms and muscle rigidity and for management of various complications including respiratory failure, acute kidney injury (AKI), autonomic dysfunction and healthcare-associated infections (HCAIs). Short incubation period (<7 days), short onset time (<3 days), autonomic dysfunction and cephalic tetanus are reported predictors of mortality [3, 4]. Human tetanus immunoglobulin (HTIG) is one of the pillars in management and combined use of intramuscular and intrathecal HTIG is associated with improved outcome [5–7]. Despite being rampant in developing economies, there is paucity of data on post-neonatal tetanus cases treated in PICU of resource-limited settings, especially India [1, 7–15]. Therefore, this study was planned to analyze clinical profile, treatment, complications, intensive care needs, outcome and predictors of mortality in children with post-neonatal tetanus admitted to a PICU. MATERIALS AND METHODS This was a retrospective study conducted in PICU of a tertiary care teaching hospital in North India. All children, 1 month to 12 years, admitted to PICU from January 2006 to December 2015 with diagnosis of post-neonatal tetanus were included. Our PICU is a medical ICU with 15 beds having facilities for ventilation and invasive and noninvasive monitoring. In recent years, total PICU admissions have been around 800–900 cases/year. The nurse to patient ratio is 1:1 for ventilated patients and 1:2 for non-ventilated patients. The diagnosis of post-neonatal tetanus was clinical (i.e. presence of trismus, risus sardonicus and/or provoked or unprovoked spasms) [1]. All cases were treated according to management protocol for tetanus used in our PICU [1]. Ethical clearance was sought from the institute ethics committee. Data were retrieved from case records and entered on a structured proforma. Information on demographics, portal of entry, vaccination status, type and Ablett’s severity grade, incubation period, period of onset, duration of illness, clinical features, treatment, complications, duration of PICU stay, outcome and follow up were recorded. Incubation period was defined as interval between acute injury and first symptom, while period of onset was taken as interval between first symptom and first spasm [1, 13]. Details regarding wound debridement and antibiotics, removal of unbound toxin (HTIG, intramuscular with/without intrathecal), control of spasms (benzodiazepines and muscle relaxants), control of autonomic dysfunction (morphine and magnesium sulfate) and supportive care (ventilation, inotropes, tracheostomy and peritoneal dialysis) were noted. Complications related to tetanus and PICU stay were included. Outcome (survival or death), length of PICU stay, status at discharge and follow up were also noted. STATISTICAL ANALYSIS Data entry and statistical analysis were performed on Microsoft Excel 2010 (Microsoft excel, Redmond, WA) and SPSS software version 21 (IBM SPSS, Armonk, NY). Descriptive statistics (mean, SD, median, range and percentages) were used for baseline variables. Survivors and non-survivors were compared using Chi-square test or Fisher exact test for dichotomous outcomes and Student t-test for continuous variables. Univariate and multivariate analyses were done for predictors of mortality. p < 0.05 was taken as significant. RESULTS A total of 30 patients with post-neonatal tetanus were identified of 6176 PICU admissions during study period (0.48% of total admission) (Fig. 1). There were 23 (76.7%) boys with a mean (±SD) age of 7.2 (±2.9) years. More than half (17, 56.7%) were completely unimmunized (Table 1). Most common portal of entry was chronic suppurative otitis media (CSOM) (n = 16, 53.3%) followed by acute injury (n = 10, 33.3%). Incubation period in cases with injury was 7 (±2.2) days. Duration of illness before presentation and period of onset were 5.6 (±3.5) and 3.8 (±2.7) days, respectively. All patients had generalized spasms at the time of admission. Other features noted are shown in Table 1. All patients had generalized tetanus with Ablett’s severity Grade IIIa (36.7%) and Grade IIIb (63.3%) (Table 1). Table 1 Clinical characteristics of cases with tetanus admitted to PICU Characteristics  Number of cases (n = 30)  Age in years, mean (SD)  7.2 (2.9)  Male gender, n (%)  23 (76.7)  PRISM III, median (IQR)  15.4 (10-32)  Vaccination status     Complete vaccination  0   Not vaccinated, n (%)  17 (56.7)   Partial vaccination, n (%)  8 (26.7)   Status not known, n (%)  5 (16.7)  Portal of entry     CSOM, n (%)  16 (53.3)   Duration of CSOM in months, mean (SD)  15.32 (11.3)   Injury, n (%)  10 (33.3)   Lower limbs, n (%)  6 (20)   Head and neck area, n (%)  2 (6.7)   Upper limb, n (%)  1 (3.3)   No injury, n (%)  4 (13.3)  Incubation period in days for cases with injury, mean (SD)  7 (2.2)  Duration of illness in days, mean (SD)  5.6 (3.5)  Period of onset in days, mean (SD)  3.8 (2.7)  Clinical features     Generalized spasms, n (%)  30 (100)   Trismus, n (%)  28 (93.3)   Jaw pain, n (%)  23 (76.7)   Risus sardonicus, n (%)  21 (70)   Opisthotonus, n (%)  20 (66.7)   Cervical rigidity, n (%)  16 (53.3)   Dysphagia, n (%)  14 (46.7)   Body ache, n (%)  6 (20)   Fever, n (%)  4 (13.3)   Dysarthria, n (%)  3 (10)   Laryngospasms, n (%)  2 (6.6)  Type of tetanus     Generalized, n (%)  30 (100)   Cervical, n (%)  0   Localized, n (%)  0  Severity of tetanus     Grade IIIa, n (%)  11 (36.7)   Grade IIIb, n (%)  19 (63.3)  Characteristics  Number of cases (n = 30)  Age in years, mean (SD)  7.2 (2.9)  Male gender, n (%)  23 (76.7)  PRISM III, median (IQR)  15.4 (10-32)  Vaccination status     Complete vaccination  0   Not vaccinated, n (%)  17 (56.7)   Partial vaccination, n (%)  8 (26.7)   Status not known, n (%)  5 (16.7)  Portal of entry     CSOM, n (%)  16 (53.3)   Duration of CSOM in months, mean (SD)  15.32 (11.3)   Injury, n (%)  10 (33.3)   Lower limbs, n (%)  6 (20)   Head and neck area, n (%)  2 (6.7)   Upper limb, n (%)  1 (3.3)   No injury, n (%)  4 (13.3)  Incubation period in days for cases with injury, mean (SD)  7 (2.2)  Duration of illness in days, mean (SD)  5.6 (3.5)  Period of onset in days, mean (SD)  3.8 (2.7)  Clinical features     Generalized spasms, n (%)  30 (100)   Trismus, n (%)  28 (93.3)   Jaw pain, n (%)  23 (76.7)   Risus sardonicus, n (%)  21 (70)   Opisthotonus, n (%)  20 (66.7)   Cervical rigidity, n (%)  16 (53.3)   Dysphagia, n (%)  14 (46.7)   Body ache, n (%)  6 (20)   Fever, n (%)  4 (13.3)   Dysarthria, n (%)  3 (10)   Laryngospasms, n (%)  2 (6.6)  Type of tetanus     Generalized, n (%)  30 (100)   Cervical, n (%)  0   Localized, n (%)  0  Severity of tetanus     Grade IIIa, n (%)  11 (36.7)   Grade IIIb, n (%)  19 (63.3)  Fig. 1. View largeDownload slide Study flow diagram. Fig. 1. View largeDownload slide Study flow diagram. Wound debridement was required in 9 of 10 (90%) cases with injury. All cases received tetanus toxoid and intramuscular HTIG (500 U). We started using intrathecal HTIG from 2012, and seven (23.3%) cases received it in doses of 1000 U. All patients were treated with appropriate antibiotics [crystalline penicillin in 23 (76.7%) or metronidazole in 7 (23.3%)] (Table 2). Table 2 Treatment details Treatment details  Number of cases (n = 30)  Wound debridement among those with injury, n (%)  9 (30)  Tetanus toxoid, n (%)  30 (100)  HTIG, n (%)  30 (100)  Intrathecal HTIG, n (%)  7 (23.3)  Antibiotic     Crystalline Penicillin, n (%)  23 (76.7)   Metronidazole, n (%)  7 (23.3)   Midazolam, n (%)  6 (20)   Duration in days, mean (SD)  2.6 (1.3)   Diazepam, n (%)  30 (100)   Duration in days, mean (SD)  20.7 (10.5)   Morphine, n (%)  29 (96.7)   Duration in days, mean (SD)  15.59 (9.1)   Magnesium sulfate, n (%)  26 (86.7)   Duration in days, mean (SD)  14.84 (9.2)   Muscle relaxant, n (%)  21 (70)   Duration in days, mean (SD)  6.84 (2.4)   Intubation, n (%)  30 (100)   Ventilation, n (%)  30 (100)   Duration in days, mean (SD)  16 (6.2)   Tracheostomy, n (%)  12 (40)   On day of PICU stay, mean (SD)  12.3 (5.1)   Inotropes, n (%)  20 (66.7)   Duration in days, mean (SD)  3.87 (2.1)   Peritoneal dialysis, n (%)  10 (33.3)  Treatment details  Number of cases (n = 30)  Wound debridement among those with injury, n (%)  9 (30)  Tetanus toxoid, n (%)  30 (100)  HTIG, n (%)  30 (100)  Intrathecal HTIG, n (%)  7 (23.3)  Antibiotic     Crystalline Penicillin, n (%)  23 (76.7)   Metronidazole, n (%)  7 (23.3)   Midazolam, n (%)  6 (20)   Duration in days, mean (SD)  2.6 (1.3)   Diazepam, n (%)  30 (100)   Duration in days, mean (SD)  20.7 (10.5)   Morphine, n (%)  29 (96.7)   Duration in days, mean (SD)  15.59 (9.1)   Magnesium sulfate, n (%)  26 (86.7)   Duration in days, mean (SD)  14.84 (9.2)   Muscle relaxant, n (%)  21 (70)   Duration in days, mean (SD)  6.84 (2.4)   Intubation, n (%)  30 (100)   Ventilation, n (%)  30 (100)   Duration in days, mean (SD)  16 (6.2)   Tracheostomy, n (%)  12 (40)   On day of PICU stay, mean (SD)  12.3 (5.1)   Inotropes, n (%)  20 (66.7)   Duration in days, mean (SD)  3.87 (2.1)   Peritoneal dialysis, n (%)  10 (33.3)  All patients initially received intravenous diazepam infusion (5–40 mg/kg/day) for spasm control followed by oral diazepam for duration of 20.7 (±10.5) days once spasms were controlled. Morphine and magnesium sulfate infusions were used for control of autonomic dysfunction: the former was used in 29 (96.7%) cases for 15.6 (±9.1) days in doses of 20–50 µg/kg/h and the latter in 26 (86.7%) cases for 14.8 (±9.2) days in doses of 100–200 mg/kg/day. For spasms refractory to above therapy, neuromuscular blocking agents were used (n = 21, 70%) for 6.8 (±2.4) days. All children were ventilated for 16 (±6.2) days. Tracheostomy was done in 12 (40%) at 12.3 (±5.1) days of admission. Vasoactive drugs were used in 20 (66.7%) cases (Table 2). All cases had one or other complication related to primary disease or therapy (Table 3). Most common was respiratory failure followed by rhabdomyolysis, AKI, autonomic dysfunction and HCAIs (Table 3). Of three cases with cardiac arrest, two survived. Table 3 Complications related to tetanus and PICU stay Complications  Number of cases (n = 30)  Number of patients with complications, n (%)  30 (100)  Rhabdomyolysis, n (%)  23 (76.7)  AKI, n (%)  19 (63.3)  Respiratory complications  30 (100)   Respiratory failure, n (%)  28 (93.3)   Laryngospasm, n (%)  2 (6.7)   Aspiration pneumonia, n (%)  1 (3.3)  Autonomic dysfunction, n (%)  19 (63.3)  On day of admission, mean (SD)  6.2 (3.7)   Bradycardia, n (%)  8 (26.7)   Hypotension, n (%)  7 (23.3)   Hypertension, n (%)  6 (20)   Diaphoresis, n (%)  5 (16.7)   Cardiac arrest, n (%)  3 (10)  Healthcare-associated infections  14 (46.7)   Ventilator-associated pneumonia, n (%)  9 (30)   Blood stream infection, n (%)  6 (20)   Urinary tract infection, n (%)  5 (16.7)  Paralytic ileus, n (%)  5 (16.7)  Pneumothorax, n (%)  3 (10)  Bed sores, n (%)  2 (6.7)  Deep venous thrombosis, n (%)  1 (3.3)  Complications  Number of cases (n = 30)  Number of patients with complications, n (%)  30 (100)  Rhabdomyolysis, n (%)  23 (76.7)  AKI, n (%)  19 (63.3)  Respiratory complications  30 (100)   Respiratory failure, n (%)  28 (93.3)   Laryngospasm, n (%)  2 (6.7)   Aspiration pneumonia, n (%)  1 (3.3)  Autonomic dysfunction, n (%)  19 (63.3)  On day of admission, mean (SD)  6.2 (3.7)   Bradycardia, n (%)  8 (26.7)   Hypotension, n (%)  7 (23.3)   Hypertension, n (%)  6 (20)   Diaphoresis, n (%)  5 (16.7)   Cardiac arrest, n (%)  3 (10)  Healthcare-associated infections  14 (46.7)   Ventilator-associated pneumonia, n (%)  9 (30)   Blood stream infection, n (%)  6 (20)   Urinary tract infection, n (%)  5 (16.7)  Paralytic ileus, n (%)  5 (16.7)  Pneumothorax, n (%)  3 (10)  Bed sores, n (%)  2 (6.7)  Deep venous thrombosis, n (%)  1 (3.3)  Twelve (40%) children died. The duration of PICU stay among survivors and non-survivors was 22.2 (±10.3) and 7.7 (±5.9) days, respectively. We were able to follow up 14 (46.7%) survivors for a duration of 5.6 (±3.8) months of which 13 were well and 1 had post-cardiac arrest neurological sequelae at the time of last follow up (Table 4). Univariate and multivariate logistic regression analyses revealed that severity Grade IIIb, autonomic dysfunction, those who did not receive intrathecal HTIG and requirement of vasoactive drugs were significantly associated with mortality (Table 5). Table 4 Outcome and follow up details Outcome and follow up details  Number of cases (n = 30)  Outcome     Survived, n (%)  18 (60)   Died, n (%)  12 (40)   Duration of PICU stay among survivors in days, mean (SD)  22.2 (10.3)   Duration of PICU stay among non-survivors in days, mean (SD)  7.8 (5.9)  Status at discharge     Well, n (%)  16 (53.3)   Discharged with sequelae, n (%)  2 (6.7)   Number of cases followed up, n (%)  14 (46.7)   Duration in months after discharge from PICU, mean (SD)  5.62 (3.8)  Status at follow up     Well, n (%)  13 (43.3)   With sequelae, n (%)  1 (3.3)  Outcome and follow up details  Number of cases (n = 30)  Outcome     Survived, n (%)  18 (60)   Died, n (%)  12 (40)   Duration of PICU stay among survivors in days, mean (SD)  22.2 (10.3)   Duration of PICU stay among non-survivors in days, mean (SD)  7.8 (5.9)  Status at discharge     Well, n (%)  16 (53.3)   Discharged with sequelae, n (%)  2 (6.7)   Number of cases followed up, n (%)  14 (46.7)   Duration in months after discharge from PICU, mean (SD)  5.62 (3.8)  Status at follow up     Well, n (%)  13 (43.3)   With sequelae, n (%)  1 (3.3)  Table 5 The predictors of mortality according to univariate and multivariate logistic regression analyses Predictor variables  Survivors (n = 18)  Non-survivors (n = 12)  Univariate analysis  Multivariate analysis  Age      0.052    ≤7 years, n (%)  11 (61.1)  3 (25)      >7 years, n (%)  7 (38.9)  9 (75)      Incubation period in days, mean (SD)  7.14 (1.57)  6.5 (4.9)  0.74    Period of onset in days, mean (SD)  4.27 (3.67)  3.08 (2.23)  0.33    Duration of illness in days, mean (SD)  6.38 (3.87)  4.58 (2.67)  0.18    ≤7 days, n (%)  12 (66.7)  8 (66.7)  0.91    >7 days, n (%)  6 (29.4)  4 (33.3)      Portal of entry      0.27     Head and neck, n (%)  11 (64.7)  6 (50)       Others, n (%)  6 (33.3)  6 (50)      Severity of tetanus      0.008  0.01   Grade IIIa, n (%)  10 (55.6)  1 (8.3)       Grade IIIb, n (%)  8 (44.4)  11 (91.7)      Intrathecal HTIG      0.013  0.004   Yes, n (%)  7 (38.9)  0 (0)       No, n (%)  11 (61.1)  12 (100)      Use of inotropes      0.001  0.002   Yes, n (%)  8 (44.4)  12 (100)       No, n (%)  10 (55.6)  0 (0)      Autonomic dysfunction      0.008  0.02   Yes, n (%)  8 (44.4)  11 (91.7)       No, n (%)  10 (55.6)  1 (8.3)      Rhabdomyolysis      0.19     Yes, n (%)  13 (72.2)  11 (91.7)       No, n (%)  5 (27.8)  1 (8.3)      AKI      0.06     Yes, n (%)  9 (50)  10 (83.3)       No, n (%)  9 (50)  2 (16.7)      HCAIs      0.76     Yes, n (%)  8 (44.4)  6 (50)       No, n (%)  10 (55.6)  6 (50)      Ventilator associated pneumonia      0.25     Yes, n (%)  4 (22.2)  5 (41.7)       No, n (%)  14 (77.8)  7 (58.3)      Predictor variables  Survivors (n = 18)  Non-survivors (n = 12)  Univariate analysis  Multivariate analysis  Age      0.052    ≤7 years, n (%)  11 (61.1)  3 (25)      >7 years, n (%)  7 (38.9)  9 (75)      Incubation period in days, mean (SD)  7.14 (1.57)  6.5 (4.9)  0.74    Period of onset in days, mean (SD)  4.27 (3.67)  3.08 (2.23)  0.33    Duration of illness in days, mean (SD)  6.38 (3.87)  4.58 (2.67)  0.18    ≤7 days, n (%)  12 (66.7)  8 (66.7)  0.91    >7 days, n (%)  6 (29.4)  4 (33.3)      Portal of entry      0.27     Head and neck, n (%)  11 (64.7)  6 (50)       Others, n (%)  6 (33.3)  6 (50)      Severity of tetanus      0.008  0.01   Grade IIIa, n (%)  10 (55.6)  1 (8.3)       Grade IIIb, n (%)  8 (44.4)  11 (91.7)      Intrathecal HTIG      0.013  0.004   Yes, n (%)  7 (38.9)  0 (0)       No, n (%)  11 (61.1)  12 (100)      Use of inotropes      0.001  0.002   Yes, n (%)  8 (44.4)  12 (100)       No, n (%)  10 (55.6)  0 (0)      Autonomic dysfunction      0.008  0.02   Yes, n (%)  8 (44.4)  11 (91.7)       No, n (%)  10 (55.6)  1 (8.3)      Rhabdomyolysis      0.19     Yes, n (%)  13 (72.2)  11 (91.7)       No, n (%)  5 (27.8)  1 (8.3)      AKI      0.06     Yes, n (%)  9 (50)  10 (83.3)       No, n (%)  9 (50)  2 (16.7)      HCAIs      0.76     Yes, n (%)  8 (44.4)  6 (50)       No, n (%)  10 (55.6)  6 (50)      Ventilator associated pneumonia      0.25     Yes, n (%)  4 (22.2)  5 (41.7)       No, n (%)  14 (77.8)  7 (58.3)      Note: Bold characters show significant p-value. DISCUSSION The present study recorded a 0.48% prevalence of post-neonatal tetanus among children admitted to PICU of a tertiary care teaching hospital in North India over a period of 10 years. Generalized spasms, trismus, jaw pain, risus sardonicus, opisthotonus, cervical rigidity, dysphagia, body ache, fever, dysarthria were common clinical features in our patients similar to that noted by other authors [1, 7–15]. All patients had generalized tetanus. None of the cases were completely immunized, a finding documented in other studies too from developing counties [1, 7–15]. Portal of entry was identified in 86.7% cases, the most common being CSOM followed by acute injury. There was no identifiable portal of entry in 13.3% cases. This pattern is also similar to other studies involving children with post-neonatal tetanus [7, 8, 10, 14, 16]. Mishra et al. [14] in a retrospective review of 77 children with post-neonatal tetanus identified that otogenic route of infection (58.4%) and trauma (23.3%) were most common portals of entry. Narang et al. [7] studied 70 children with post-neonatal tetanus, and found that 64 (91.4%) had an identifiable portal of entry: ear discharge in 60% (42 of 70) and acute wound in 31.4% (22 of 70). Other studies identified lower limb injury as the commonest portal of entry [15–17]. All cases received appropriate antibiotics, tetanus toxoid and intramuscular HTIG and few received intrathecal HTIG (n = 7, 23.3%). All cases required diazepam (intravenous infusion followed by oral, for 3 weeks) and morphine and magnesium sulfate infusion (for 2 weeks each). Similarly, all cases also required ventilation for around 2–3 weeks. The duration of requirement of intensive care and supportive therapy corresponds to natural history of tetanus where active spasms are known to last for 2–3 weeks [1]. The common complications noted were respiratory failure, rhabdomyolysis, AKI, autonomic dysfunction (in second week of illness) and HCAIs. Rhabdomyolysis in tetanus is due to generalized muscle spasms. Myoglobinuria, hypotension, diazepam and sepsis can lead to AKI [9, 15]. Respiratory complications are due to spasms, laryngospasm, aspiration and heavy sedation. Autonomic imbalances (bradycardia/tachycardia, hypotension/hypertension and sudden cardiac arrest), HCAIs, paralytic ileus, decubitus ulcer and constipation have been reported in various studies [1, 3, 9–11] as noted in index study. We however documented a higher proportion of cases having autonomic dysfunction (63%) unlike an adult study where it was present in only one-third of patients (3). The mortality rate (40%) in the current study was within the range reported by other studies from developing countries (4.1–78.9%) [10–15]. Ours being a tertiary referral center catering to a wide region, the sickest cases are referred to us, thus explaining the high mortality seen in our cohort. Deaths occurred at the end of the first week of PICU stay (7.8 ± 5.9 days); immediate cause of death being refractory shock due to sepsis and autonomic dysfunction (n = 6), sudden cardiac arrest due to autonomic dysfunction (n = 3), pneumothorax (n = 2) and multifactorial (n = 1). We found that the non-survivors had more severe illness (Grade IIIb), autonomic dysfunction, had not received intrathecal HTIG and required vasoactive drugs. Aggarwal et al. [12] in a study involving 57 children documented that autonomic dysfunction was seen in 17.5% cases and was significantly associated with mortality (p = 0.025). Wasay et al. [3] studied 96 adults with tetanus and documented that autonomic dysfunction even in mild or moderate tetanus, irrespective of the need for mechanical ventilation, predicted poor outcome (59). Age, incubation period, duration of illness, period of onset, site of injury, AKI or HCAIs did not have any association with mortality in our cohort unlike few studies in which shorter incubation and period of onset were associated with mortality [4, 12, 18]. We observed that use of intrathecal HTIG along with intramuscular HTIG was associated with good outcome. Our findings were similar to that of Narang et al. [7] who in their retrospective study of 70 post-neonatal tetanus, found that mortality was higher (25%, 7 of 28) in those who received intramuscular HTIG alone as compared with those who received both intramuscular and intrathecal HTIG (4.7%, 2 of 42) (p = 0.025). Other studies have also demonstrated the superiority of intrathecal and intramuscular administration of HTIG as compared with intramuscular route alone [5, 6]. Miranda-Filho et al. [5] from a Brazilin study involving 120 patients with tetanus demonstrated better clinical outcomes in the form of shortened duration of spasms, hospital stay and respiratory assistance in patients who received combined intrathecal and intramuscular HTIG when compared with intramuscular route alone. Kabura et al. [6] in a meta-analysis involving 12 trials (n= 942; 484 in intrathecal group and 458 in intramuscular group) demonstrated that intrathecal HTIG or equine tetanus antitoxin was superior to intramuscular in preventing mortality (Relative risk: 0.71, 95% confidence interval: 0.62, 0.81). Intrathecal therapy retained its superiority in both adults and neonates and also for high and low dose. Intrathecal HTIG binds faster to the toxins released by C. tetani in central nervous system and neutralizes it in a better way as compared with intramuscular HTIG [6]. Prolonged hospitalization (around 3 weeks) was similar to that reported in other studies [9, 12, 15]. Half of the survivors (53.3%) were discharged with good neurological status; only one had post-cardiac arrest neurological sequelae at the time of the last follow up. This study summarizes the demographic, clinical profile, treatment and complications of post-neonatal tetanus in PICU over a period of 10 years from a resource-limited set up where data are scarce despite the disease being a major public health problem. Use of intrathecal HTIG may be associated with better survival. Despite intensive care, the mortality continues to be high, thus reiterating the need for prevention with better immunization coverage. We were able to follow three-fourth (14 of 18) of the discharged patients for a period of 6 months, and the outcome was good. The study however suffers from all limitations of a retrospective study. CONCLUSION Tetanus is still a major public health problem in developing countries including India. Improving routine immunization coverage, prompt treatment of CSOM, appropriate wound management are paramount for prevention of tetanus. Management includes control of spasms, respiratory and hemodynamic support and treatment of autonomic dysfunction and complications. Mortality remains high despite PICU care. Combined use of intrathecal and intramuscular HTIG is superior to intramuscular HTIG alone in reducing mortality. References 1 Singhi S, Jain V, Subramanian C. Post-neonatal tetanus: issues in intensive care management. Indian J Pediatr  2001; 68: 267– 72. Google Scholar CrossRef Search ADS PubMed  2 Vandelaer J, Birmingham M, Gasse F, et al.   Tetanus in developing countries: an update on the Maternal and Neonatal Tetanus Elimination Initiative. Vaccine  2003; 21: 3442– 5. Google Scholar CrossRef Search ADS PubMed  3 Wasay M, Khealani BA, Talati N, et al.   Autonomic nervous system dysfunction predicts poor prognosis in patients with mild to moderate tetanus. BMC Neurol  2005; 5: 2. Google Scholar CrossRef Search ADS PubMed  4 Bhatia R, Prabhakar S, Grover VK. Tetanus. Neurol India  2002; 50: 398– 407. Google Scholar PubMed  5 Miranda-Filho Dde B, Ximenes RA, Barone AA, et al.   Randomised controlled trial of tetanus treatment with antitetanus immunoglobulin by the intrathecal or intramuscular route. BMJ  2004; 328: 615. Google Scholar CrossRef Search ADS PubMed  6 Kabura L, Ilibagiza D, Menten J, et al.   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. Google Scholar CrossRef Search ADS PubMed  7 Narang M, Khurana A, Gomber S, et al.   Epidemiological trends of tetanus from East Delhi, India: a hospital-based study. J Infect Public Health  2014; 7: 121– 4. Google Scholar CrossRef Search ADS PubMed  8 Mondal T, Aneja S, Tyagi A, et al.   A study of childhood tetanus in post-neonatal age group in Delhi. Indian Pediatr  1994; 31: 1369– 72. Google Scholar PubMed  9 Tullu MS, Deshmukh CT, Kamat JR. Experience of pediatric tetanus cases from Mumbai. Indian Pediatr  2000; 37: 765– 71. Google Scholar PubMed  10 Geeta MG, Krishnakumar P, Mathews L. Intrathecal tetanus immunoglobulins in the management of tetanus. Indian J Pediatr  2007; 74: 43– 5. Google Scholar CrossRef Search ADS PubMed  11 Poudel P, Singh R, Raja S, et al.   Pediatric and neonatal tetanus: a hospital based study at eastern Nepal. Nepal Med Coll J  2008; 10: 170– 5. Google Scholar PubMed  12 Aggarwal M, Sood V, Aggarwal KC. Tetanus in pediatric patients–predictors affecting mortality and role of immunoglobulin. Indian Pediatr  2011; 48: 987– 8. Google Scholar PubMed  13 Oyedeji OA, Fadero F, Joel-Medewase V, et al.   Trends in neonatal and post-neonatal tetanus admissions at a Nigerian teaching hospital. J Infect Dev Ctries  2012; 6: 847– 53. Google Scholar CrossRef Search ADS PubMed  14 Mishra K, Basu S, Kumar D, et al.   Tetanus - still a scourge in the 21st century: a paediatric hospital-based study in India. Trop Doct  2012; 42: 157– 9. Google Scholar CrossRef Search ADS PubMed  15 Animasahun BA, Gbelee OH, Ogunlana AT, et al.   Profile and outcome of patients with post-neonatal tetanus in a tertiary centre in south west Nigeria: any remarkable reduction in the scourge?. Pan Afr Med J  2015; 21: 254. Google Scholar CrossRef Search ADS PubMed  16 Lau LG, Kong KO, Chew PH. A ten-year retrospective study of tetanus at a general hospital in Malaysia. Singapore Med J  2001; 42: 346– 50. Google Scholar PubMed  17 Onwuekwe IO, Onyedum CC, Nwabueze AC. Experience with tetanus in a tertiary hospital in south east Nigeria. Niger J Med  2008; 17: 50– 2. Google Scholar CrossRef Search ADS PubMed  18 Cook TM, Protheroe RT, Handel JM. Tetanus: a review of the literature. Br J Anaesth  2001; 87: 477– 87. Google Scholar CrossRef Search ADS PubMed  © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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Journal of Tropical PediatricsOxford University Press

Published: Feb 1, 2018

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