Kishore Pichamuthu

Bioscavenger therapy for organophosphate poisoning – an open-labeled pilot randomized trial comparing fresh frozen plasma or albumin with saline in acute organophosphate poisoning in humans

Introduction. Traditional treatment of organophosphate poisoning (OP) with oximes has had limited success. Fresh frozen plasma (FFP) or albumin, acting as bioscavengers to mop up free organophosphate, has been recently proposed as a treatment modality. In this pilot open-label, three-arm, randomized controlled study exploring proof of concept, we evaluated if bioscavenger therapy had a role in OP. Patients and methods. Sixty patients with significant poisoning presenting within 12 hours, with suppression of pseudocholinesterase activity to < 1,000 U/L, were randomized to receive FFP (8 bags, 250 mL each over 3 days), 20% human albumin (4 × 100 mL over 3 days), or saline (2,000 mL over 3 days) in addition to atropine and supportive care. Pseudocholinesterase and organophosphate levels were measured pretreatment, post-infusion (Day 2, Day 3), and predischarge and expressed as mean ± standard error. The incidence of intermediate syndrome, need for mechanical ventilation, atropine requirement, and mortality were assessed. Results. Twenty patients received albumin and 19 patients each FFP or saline. FFP increased pseudocholinesterase levels (250 ± 44–1,241 ± 364 U/L) significantly (p = 0.007). Small, nonsignificant increases were observed with saline (160 ± 30–259 ± 78) and albumin (146 ± 18–220 ± 61). Organophosphate levels reduced in all 3 arms; no clear-cut trends were observed. We observed more cases of intermediate syndrome with FFP [10/19 (53%) vs. 5/20 (25%) vs. 5/19 (26%), FFP, albumin, and saline arms (p = 0.15)]. The interventions did not affect ventilatory requirements (14/19 vs. 15/20 vs. 14/19) or prevent delayed intubation. There were no differences in mean (±standard error) atropine requirement (in milligrams) in the first 3 days (536 ± 132 vs. 361 ± 125 vs. 789 ± 334) and duration (in days) of ventilation (10.0 ± 2.1 vs. 7.1 ± 1.5 vs. 7.5 ± 1.5) or hospital stay (12.4 ± 2.2 vs. 9.8 ± 1.4 vs. 9.8 ± 1.6). Two patients developed adverse effects with FFP. Mortality was similar (4/19 vs. 5/20 vs. 2/19, p = 0.6). Conclusions. Despite significant increase in pseudocholinesterase levels with FFP, this pilot study did not demonstrate favorable trends in clinical outcomes with FFP or albumin.

Profile of organ dysfunction and predictors of mortality in severe scrub typhus infection requiring intensive care admission

Background and Aims: Scrub typhus, a zoonotic rickettsial infection, is an important reason for intensive care unit (ICU) admission in the Indian subcontinent. We describe the clinical profile, organ dysfunction, and predictors of mortality of severe scrub typhus infection. Materials and Methods: Retrospective study of patients admitted with scrub typhus infection to a tertiary care university affiliated teaching hospital in India during a 21-month period. Results: The cohort (n = 116) aged 40.0 ± 15.2 years (mean ± SD), presented 8.5 ± 4.4 days after symptom onset. Common symptoms included fever (100%), breathlessness (68.5%), and altered mental status (25.5%). Forty-seven (41.6%) patients had an eschar. Admission APACHE-II score was 19.6 ± 8.2. Ninety-one (85.2%) patients had dysfunction of 3 or more organ systems. Respiratory (96.6%) and hematological (86.2%) dysfunction were frequent. Mechanical ventilation was required in 102 (87.9%) patients, of whom 14 (12.1%) were solely managed with non-invasive ventilation. Thirteen patients (11.2%) required dialysis. Duration of hospital stay was 10.7 ± 9.7 days. Actual hospital mortality (24.1%) was less than predicted APACHE-II mortality (36%; 95% Confidence interval 32-41). APACHE-II score and duration of fever were independently associated with mortality on logistic regression analysis. Conclusions: In this cohort of severe scrub typhus infection with multi-organ dysfunction, survival was good despite high severity of illness scores. APACHE-II score and duration of fever independently predicted mortality.

Delayed-onset encephalopathy and coma in acute organophosphate poisoning in humans

The objective of the study was to describe the clinical characteristics and course of delayed-onset organophosphate (OP) poisoning. In our clinical experience, we have noticed patients with onset of deep coma 4-7 days after hospital admission, clinical features that have not been previously described. We set up a prospective observational study over 1 year to formally characterize this observation. Thirty-five patients admitted to the intensive care unit (ICU) with severe OP poisoning and treated with atropine and supportive therapy were followed up. Oximes were not administered. Three patients developed delayed-onset coma after presenting with normal or near normal Glasgow coma score (GCS). They developed altered conscious state rapidly progressing to deep coma, 5.0+/-1.0 (mean+/-S.D.) days after OP ingestion. The GCS persisted at 2T for 4.3+/-2.1 days despite the cessation of sedative drugs at the onset of coma. During this period, the patients had miosed non-reacting pupils and no clinically detectable cortical or brainstem activity. Computed tomography of the brain and cerebrospinal fluid analysis were normal. Electroencephalogram showed bihemispheric slow wave disturbances. Two patients required atropine during this period to maintain heart rate and reduce secretions. In all three patients, no metabolic, infective or non-infective cause of altered conscious state was identified. With supportive therapy the GCS improved to 10T in 8.0+/-2.0 days. All patients survived to hospital discharge. Three other patients who developed a reduction in GCS (3T-7T) by 4.7+/-1.2 days but not progressing to coma and recovering (GCS 10T) in 3.3+/-0.6 days may have manifested delayed-onset encephalopathy. Delayed-onset coma appears to have a distinct clinical profile and course with complete resolution of symptoms with supportive therapy. Although persistent cholinesterase inhibition is likely to have contributed to the manifestations, the mechanism of coma and encephalopathy need to be explored in further trials. The good outcomes in these patients suggest that therapy should not be limited in OP-poisoned patients developing profound coma or encephalopathy during hospitalization.

Cardiac manifestations in patients with pandemic (H1N1) 2009 virus infection needing intensive care

PURPOSE To characterize the cardiac manifestations in severe pandemic (H1N1) 2009 virus [P(H1N1)2009v] infection. MATERIALS AND METHODS Adult patients admitted to the intensive care unit were recruited. Patients with an elevated troponin I (>1.5 ng/mL) and those requiring vasoactive agents had an echocardiogram. Myocardial injury was defined as elevated troponin I. Patients with reduced ejection fraction lower than 50% were diagnosed as having left ventricular systolic dysfunction. Myocarditis was presumed when myocardial injury was associated with global myocardial dysfunction. Myocardial injury and dysfunction were correlated with mortality and expressed as odds ratio (OR) with 95% confidence intervals (CI). RESULTS Thirty-seven patients presented at 6.4 (SD 3.2) days of illness. Four patients had valvular heart disease and 1 preexisting ischemic heart disease. Seventeen (46%) patients had evidence of myocardial injury. Twenty of 28 patients in whom an echocardiogram was clinically indicated had left ventricular systolic dysfunction. Of these, 14 patients were diagnosed as having myocarditis, and most of them (12 patients) developed it early. Myocarditis was associated with longer duration of vasoactive agents (OR 1.46, 95% CI 1.06-2.02) and mortality. Patients with elevated troponin I had an increased risk of death (OR 8.7, 95% CI 1.5-60). A higher mortality was observed in patients with left ventricular systolic dysfunction (OR 9.6, 95% CI 1.7-58) compared with those in whom an echocardiogram was normal or not indicated. CONCLUSION In our cohort of severe P(H1N1)2009v infection, myocardial injury and dysfunction was frequent and associated with high mortality.

Clinical Profile and Predictors of Mortality of Severe Pandemic (H1N1) 2009 Virus Infection Needing Intensive Care: A Multi-Centre Prospective Study from South India.

Background: This multi-center study from India details the profile and outcomes of patients admitted to the intensive care unit (ICU) with pandemic Influenza A (H1N1) 2009 virus [P(H1N1)2009v] infection. Materials and Methods: Over 4 months, adult patients diagnosed to have P(H1N1)2009v infection by real-time RT-PCR of respiratory specimens and requiring ICU admission were followed up until death or hospital discharge. Sequential organ failure assessment (SOFA) scores were calculated daily. Results: Of the 1902 patients screened, 464 (24.4%) tested positive for P(H1N1)2009v; 106 (22.8%) patients aged 35±11.9 (mean±SD) years required ICU admission 5.8±2.7 days after onset of illness. Common symptoms were fever (96.2%), cough (88.7%), and breathlessness (85.9%). The admission APACHE-II and SOFA scores were 14.4±6.5 and 5.5±3.1, respectively. Ninety-six (90.6%) patients required ventilation for 10.1±7.5 days. Of these, 34/96 (35.4%) were non-invasively ventilated; 16/34 were weaned successfully whilst 18/34 required intubation. Sixteen patients (15.1%) needed dialysis. The duration of hospitalization was 14.0±8.0 days. Hospital mortality was 49%. Mortality in pregnant/puerperal women was 52.6% (10/19). Patients requiring invasive ventilation at admission had a higher mortality than those managed with non-invasive ventilation and those not requiring ventilation (44/62 vs. 8/44, P<0.001). Need for dialysis was independently associated with mortality (P=0.019). Although admission APACHE-II and SOFA scores were significantly (P<0.02) higher in non-survivors compared with survivors on univariate analysis, individually, neither were predictive on multivariate analysis. Conclusions: In our setting, a high mortality was observed in patients admitted to ICU with severe P(H1N1)2009v infection. The need for invasive ventilation and dialysis were associated with a poor outcome.

In-laws, insecticide—and a mimic of brain death

In December, 2006, a 28-year-old woman from Andhra Pradesh, India, impulsively swallowed 50 mL of phorate (a diethyl organophosphorus insecticide) after quarrelling with her husband’s family, with whom she lived. Her inlaws saw her vomit and briefl y lose consciousness—and, suspecting what she had done, took her by moped to a local hospital. The patient was given gastric lavage, before being transferred by ambulance to the emergency department at our hospital, 400 km away. The patient arrived 9 h 30 min after her suicide attempt. Her giddiness and vomiting had persisted, and she now also had abdominal pain; but she was stable. 5 h after arrival, the patient became increasingly breathless; her arterial oxygen saturation decreased to 77%, necessitating intubation and ventilation. She was transferred to our intensive-care unit. We prescribed atropine, at 4 mg/h, to counteract the eff ects of organophosphate. Although the chest radiograph was clear, we suspected that the breathlessness was caused by aspiration, and prescribed penicillin and levofl oxacin. We also prescribed morphine and lorazepam, to keep the patient comfortable but easily arousable. We titrated the dose of atropine to the patient’s heart rate, but aimed also for quiet bowel sounds, pupils that were neither contracted nor dilated, a clear-sounding chest, and a systolic blood pressure higher than 90 mm Hg. The patient recovered steadily until her 4th day in hospital, when her score on the Glasgow coma scale (GCS) decreased to 8T (fi gure), prompting us to discontinue sedation. Over the next 12 h, the patient’s limbs trembled and jerked, although she did not have seizures; we noted that the muscular tone of the limbs had increased. The GCS score then decreased to 2T over the next 12–24 h. We could not fi nd any cause for the coma, other than organophosphate poisoning, despite doing blood tests (including arterial blood gases), CT of the head, a lumbar puncture, and monitoring the patient’s arterial oxygen saturations. The serum concentration of pseudocholinesterase was 254 IU/mL (normal range 3000– 6000 IU/mL). During the coma, fi ndings on examination were largely consistent with brain death: oculocephalic, pupillary, corneal, and deep-tendon refl exes were absent; the patient did not react to painful stimuli or caloric stimulation; she did not breathe spontaneously. Unlike in brain death, however, the pupils remained constricted. An electroencephalogram showed global suppression of cortical activity. We continued to prescribe atropine. After 5 days of deep coma, the patient started to recover, and was fully conscious by day 15. She later developed pneumonia, but was discharged from the hospital, in good health, after a 39-day stay. When last seen, in March, 2007, she was well. Organophosphates inhibit acetylcholin esterase, causing overstimulation of nicotinic, muscar inic, and central acetylcholine receptors. Neurological manifestations of organophosphate poisoning range from anxiety, restlessness, and tremors to seizures, central respiratory depression, and coma. Although neurological manifestations are usually observed shortly after poisoning occurs, they can be delayed. Recognition of delayed symptoms and signs can avert unfortunate misdiagnoses, such as brain death. Phorate is lipidsoluble: we conclude that much of the swallowed insecticide was absorbed by the patient’s body fat, and released several days into her hospital stay. Patients who have swallowed lipid-soluble organophosphates may benefi t from treatment with oximes, which separate organophosphate from acetylcholinesterase, for longer than patients who have swallowed other organophosphates. By contrast, gastric lavage may not be helpful, although patients’ relatives may demand it, as a sign that all possible eff orts are being made. Most hospitals in rural India are able to provide gastric lavage and atropine—however, few are able to intubate and ventilate the patient, and many prefer to avoid the legal and administrative complications of suicide attempts. Banning the most toxic pesticides in China and India could save more than 150 000 lives a year.

A computer-assisted recording, diagnosis and management of the medically ill system for use in the intensive care unit: a preliminary report.

Background: Computerized medical information systems have been popularized over the last two decades to improve quality and safety, and for decreasing medical errors. Aim: To develop a clinician-friendly computer-based support system in the intensive care unit (ICU) that incorporates recording, reminders, alerts, checklists and diagnostic differentials for common conditions encountered in critical care. Materials and Methods: This project was carried out at the Medical ICU CMC Hospital, Vellore, in collaboration with the Computer Science Department, VIT University. The first phase was to design and develop monitoring and medication sheets. Terminologies such as checklists (intervention list that pops up at defined times for all patients), reminders (intervention unique to each patient) and alerts (time-based, value-based, trend-based) were defined. The diagnostic and intervention bundles were characterized in the second phase. The accuracy and reliability of the software to generate alerts, reminders and diagnoses was tested in the third phase. The fourth phase will be to integrate this with the hospital information system and the bedside monitors. Results: Alpha testing was performed using six scenarios written by intensivists. The software generated real-time alerts and reminders and provided diagnostic differentials relevant to critical care. Predefined interventions for each diagnostic possibility appeared as pop-ups. Problems identified during alpha testing were rectified prior to beta testing. Conclusions: The use of a computer-assisted monitoring, recording and diagnostic system appears promising. It is envisaged that further software refinements following beta testing would facilitate the improvement of quality and safety in the critical care environment.

Human poisoning with hexastar™: A hexaconazole-containing agrochemical fungicide

We report a patient who ingested 500 ml of Hexastar 5.5% EC™, a hexaconazole-containing product. Clinical toxicity consisted primarily of central nervous system depression and generalized trembling. The patient recovered without sequelae with supportive therapy.

Spectrum of cardiac manifestations and its relationship to outcomes in patients admitted with scrub typhus infection

AIM To study the spectrum of cardiac manifestations in scrub typhus infection and assess its relationship to outcomes. METHODS Demographic data, electrocardiographic (ECG) changes, left ventricular (LV) systolic and diastolic function, myocardial injury (defined as troponin T > 14 pg/mL), and pericardial effusion were documented. Myocarditis was diagnosed when myocardial injury was associated with global LV systolic dysfunction. The relationship between myocarditis and outcomes was assessed using logistic regression analysis and expressed as odds ratio (OR) with 95%CI. RESULTS The cohort (n = 81; 35 males) aged 49.4 ± 16.1 years (mean, SD) presented 8.1 ± 3.1 d after symptom onset. The APACHE-II score was 15.7 ± 7.0. Forty-eight (59%) patients were ventilated, and 46 (56%) required vasoactive agents. Mortality was 9.9%. ECG changes were non-specific; sinus tachycardia was the most common finding. Myocardial injury was evident in 61.7% of patients and LV systolic dysfunction in 30.9%. A diagnosis of myocarditis was made in 12.3%. In addition, seven patients with regional wall motion abnormalities had LV systolic dysfunction and elevated cardiac enzymes. Mild diastolic dysfunction was observed in 18 (22%) patients. Mild to moderate pericardial effusion was seen in 51%. On multivariate logistic regression analysis, patients with myocarditis tended to be older (OR = 1.04, 95%CI: 0.99-1.09), had shorter symptom duration (OR = 0.69, 95%CI: 0.49-0.98), and tended to stay longer in hospital (OR = 1.17, 95%CI: 0.98-1.40). Myocarditis was not associated with increased mortality. CONCLUSION In scrub typhus infection, cardiac manifestations are frequent and associated with increased morbidity but not mortality.

Case Report: Failure of Therapeutic Coma in Rabies Encephalitis.

Rabies encephalitis is a fulminant, almost universally fatal infection involving the central nervous system. A unique treatment protocol, including anti-exicitotoxic therapy and induced coma was credited with the survival of a vaccinated teenager with bat rabies encephalitis in 2005. However, multiple efforts to replicate this expensive and intense protocol have not been successful. In this article, we report the failure of the protocol in Indian patients with canine-acquired rabies and elucidate the potential explanations for the failure of the protocol in our patients.