Reply to Jalink, M.B. Comment on "Senthilkumaran et al. Bilateral Simultaneous Optic Neuritis Following Envenomations by Indian Cobra and Common Krait. Toxins 2022, 14, 805".

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Identifying key factors contributing to treatment costs for snakebite envenoming in private tertiary healthcare settings in Tamil Nadu, India.

BACKGROUND: India suffers ~58,000 annual deaths due to snakebites. The 'Big Four' snakes (Russell's viper, Indian cobra, common krait, and saw-scaled viper) that are responsible for most bites cause diverse clinical effects. Delayed treatment increases the risk of serious complications and treatment costs. Although government hospitals offer free treatment for snakebites in India, most patients opt for private healthcare, which is an out-of-pocket expense as they often lack health insurance coverage. This study aims to analyse snakebite treatment costs in private tertiary care hospitals in Tamil Nadu, India and identifies the key factors contributing to treatment costs. METHODOLOGY/PRINCIPAL FINDINGS: The treatment cost details for 913 snakebite victims were collected from 10 private tertiary care hospitals across Tamil Nadu. The data were classified into hospital, pharmacy, investigation, and laboratory costs, and analysed to determine various factors that contribute to the costs. The results demonstrate that the average treatment costs vary widely for different snakes. The hospital and pharmacy costs are higher than investigation and laboratory costs for all snakebites. Notably, Russell's viper bites cost significantly more than the bites from other snakes. Overall, the type of snake, nature of complications, specialist treatments required, and arrival time to hospitals were identified as some of the key factors for higher treatment costs. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that ~80% of snakebite patients can be treated with INR 100,000 (~GBP 1000 or USD 1200) or less. This study emphasises the urgent need to improve rural medical care by providing appropriate training for healthcare professionals and essential resources to facilitate early assessment of patients, administer the initial dose of antivenom and refer the patients to tertiary care only when needed. Moreover, the outcome of this study forms a basis for developing appropriate policies to regulate snakebite treatment costs and provide affordable medical insurance for vulnerable communities.

Partial segmental thrombosis of the corpus cavernosum following Russell's viper bite.

Snakebite envenoming (SBE) is common in rural communities living in tropical regions that often have fragile and/or overwhelmed healthcare systems. The complex scenarios around SBE lead to a high number of deaths, disabilities, and long-term consequences in patients. Russell's viper (Daboia russelii) is one of the most medically important snake species in India, which causes devastating pathological conditions characterised by a wide range of clinical manifestations. This broad spectrum of symptoms requires additional therapeutic interventions beyond the classical antivenom administration. Hence, positive outcomes for patients affected by SBE can be achieved with a better understanding of previous experiences describing clinical manifestations and various therapeutic interventions including for rare and underreported conditions. Here, we report an SBE victim who developed partial segmental thrombosis in the corpus cavernosum following Russell's viper envenomation and its diagnostic and treatment approaches. The patients received 180 ml of antivenom to resolve the abnormalities in their haematological parameters. Despite antivenom treatment, they developed severe pain in their genital region, and subsequent ultrasound and magnetic resonance imaging confirmed segmental thrombosis in the corpus cavernosum, which required supportive measures. The treatment using low molecular weight heparin, rivaroxaban and non-steroidal anti-inflammatory drugs resolved segmental thrombosis. In conclusion, this case report exemplifies the development of a rare segmental thrombosis in corpus cavernosum and how the medical, scientific, and general community can benefit from documenting clinical manifestations, medically relevant insights into patient care and the management of underreported complications.

Peripheral Arterial Thrombosis following Russell's Viper Bites.

Envenomings by Russell's viper ( Daboia russelii ), a species of high medical importance in India and other Asian countries, commonly result in hemorrhage, coagulopathies, necrosis, and acute kidney injury. Although bleeding complications are frequently reported following viper envenomings, thrombotic events occur rarely (reported only in coronary and carotid arteries) with serious consequences. For the first time, we report three serious cases of peripheral arterial thrombosis following Russell's viper bites and their diagnostic, clinical management, and mechanistic insights. These patients developed occlusive thrombi in their peripheral arteries and symptoms despite antivenom treatment. In addition to clinical features, computed tomography angiography was used to diagnose arterial thrombosis and ascertain its precise locations. They were treated using thrombectomy or amputation in one case that presented with gangrenous digits. Mechanistic insights into the pathology through investigations revealed the procoagulant actions of Russell's viper venom in standard clotting tests as well as in rotational thromboelastometry analysis. Notably, Russell's viper venom inhibited agonist-induced platelet activation. The procoagulant effects of Russell's viper venom were inhibited by a matrix metalloprotease inhibitor, marimastat, although a phospholipase A 2 inhibitor (varespladib) did not show any inhibitory effects. Russell's viper venom induced pulmonary thrombosis when injected intravenously in mice and thrombi in the microvasculature and affected skeletal muscle when administered locally. These data emphasize the significance of peripheral arterial thrombosis in snakebite victims and provide awareness, mechanisms, and robust strategies for clinicians to tackle this issue in patients.

Neutrophil-mediated erythrophagocytosis following Russell's viper (Daboia russelii) bite.

Snakebite envenomation is regarded as a high-priority neglected tropical disease by the World Health Organisation, as it results in significant loss of lives and permanent disabilities. Russell's viper is one of the important venomous snakes that causes morbidities, mortalities and disabilities in India. The clinical presentation of Russell's viper envenomation is characterised by local envenoming effects including tissue damage, venom-induced coagulopathy, neurotoxicity, and kidney injury. However, venom composition and its mechanisms of toxicity are highly variable even within snakes of the same species including Russell's viper. This variation in venom composition results in a broad range of clinical complications. Here, we present a previously undocumented case of neutrophil-mediated erythrophagocytosis in a healthy 28-year-old female following Russell's viper bite. Systemic envenomation effects and bleeding abnormalities in this patient were corrected by the administration of polyvalent antivenom. Two days later, the patient developed progressive swelling and ecchymosis in the bitten limb. Observed abnormal limits within blood testing were followed up by a peripheral blood smear where it was found that 30% of neutrophils had phagocytosed erythrocytes as they were found within the cytoplasm. The patient underwent a fasciotomy for compartmental syndrome and received packed red cells and a course of corticosteroids. Following this treatment, the patient made a full recovery. This case report outlines a previously undocumented pathological event induced by Russell's viper envenomation, guiding diagnosis and treatment. Clinicians' knowledge of the mechanisms of toxicity of Russell's viper envenomation and its clinical manifestations are essential for improving the treatment of snakebites to achieve positive outcomes.

Rapid identification of bilateral adrenal and pituitary haemorrhages induced by Russell's viper envenomation results in positive patient outcome.

The clinical management of snakebite envenomation (SBE) is challenging in many tropical and subtropical regions of developing countries due to the complex clinical manifestations and inadequate medical infrastructure. Some venomous snakes, such as the Indian Russell's viper (Daboia russelii) cause a wide range of rare complications in addition to their classical envenomation effects. In general, these uncommon complications are often misdiagnosed or not treated promptly due to a lack of awareness about these conditions. Thus, it is critical to report such complications to draw the attention of the healthcare and research communities to improve the clinical management and scientific research of SBE, respectively. Here, we report bilateral adrenal and pituitary haemorrhages in an SBE patient following a bite by Russell's viper in India. The initial symptoms included gum bleeding, swelling, axillary lymphadenopathy and clotting abnormalities. Despite the administration of antivenom, the patient presented palpitation, nausea, and abdominal pain, which were not recovered by combinational therapy with epinephrine and dexamethasone. Further infusion of antivenom did not address these issues and the patient displayed persistent hypotension, hypoglycaemia and hyperkalaemia suggesting an adrenal crisis. Inadequate secretion of corticosteroids was confirmed by laboratory tests, and imaging investigations revealed haemorrhages in both the adrenal and pituitary glands. The patient made a full recovery after treatment with hydrocortisone and thyroxine. This report adds to the growing evidence of rare complications induced by Russell's viper envenomations and it provides relevant guidance to diagnose and treat such complications in SBE victims.

The Effectiveness of Antibiotics in Managing Bacterial Infections on Bite Sites following Snakebite Envenomation.

Snakebite envenomation (SBE) is a life-threatening medical emergency with a high mortality rate. Common secondary complications following SBE, such as wound infections, are significant due to their impact on worsening local tissue damage and causing systemic infection. Antivenoms are not effective to treat wound infections following SBE. Moreover, in several rural clinical settings, broad-spectrum antibiotics are often used without clear guidelines or based on limited laboratory data, resulting in undesirable side effects and exacerbated treatment costs. Therefore, robust antibiotic strategies should be developed to tackle this critical issue. Currently, there is limited information available on the bacterial profiles of SBE-induced infections and antibiotic susceptibility. Hence, it is essential to improve the knowledge of bacterial profiles and their antibiotic sensitivity in SBE victims to develop better treatment strategies. This study aimed to address this issue by examining the bacterial profiles of SBE victims with a specific focus on Russell's viper envenomation. The most frequently found bacteria in the bites of SBE victims were Staphylococcus aureus, Klebsiella sp., Escherichia coli, and Pseudomonas aeruginosa. Linezolid, clindamycin, colistin, meropenem, and amikacin were some of the most effective antibiotics for commonly grown bacteria in SBE victims. Similarly, ciprofloxacin, ampicillin, amoxiclave, cefixime, and tetracyclin were the least effective antibiotics for common bacteria found in the wound swabs of SBE victims. These data provide robust guidance for infection management following SBE and offer useful insights to aid in designing effective treatment protocols for SBE with serious wound infections in rural areas where laboratory facilities may not be readily available.

Russell's viper envenomation induces rectus sheath haematoma.

Snakebite envenomation causes systemic and local manifestations, which result from the individual or synergistic actions of multiple venom components. The pathological hallmarks of medically important venomous snakes such as the Indian Russell's viper (Daboia russelii) are well known. Envenomation by Russell's viper is typically characterised by coagulopathies, muscular damage, nephrotoxicity, and neurotoxicity. However, recent reports have revealed several unusual complications that provide a better understanding of Russell's viper envenomation effects. To further strengthen this, here, we report a case of Russell's viper bite that induced acute abdominal pain, which was intensified on day two and conservatively treated under medical supervision. Both Fothergill and Carnett signs were positive for this patient. An ultrasound imaging revealed a dissimilar dense mass, and the abdominal computed tomography scan confirmed rectus sheath haematoma. The clinical management involved the administration of polyvalent antivenom, packed red blood cells, fresh frozen plasma, and platelets. The patient recovered gradually and was discharged from the hospital eight days after the bite. Overall, this case presentation shares an uncommon experience and adds new insights into the complex series of rare pathological events associated with Russell's viper bites in India. The scientific documentation of relatively infrequent entities based on an ongoing living assessment of medical experiences, for example, this rectus sheath haematoma, constitutes valuable guidance for an adequate diagnosis and timely treatment. Essential awareness among clinicians and further research on understanding the molecular relationship between Russell's viper venom and rectus sheath haematoma will improve patient outcomes and understanding of this condition, respectively.

An Unnecessary Russell's Viper Bite on the Tongue Due to Live Snake Worship and Dangerous First Aid Emphasise the Urgent Need for Stringent Policies.

India suffers the highest incidence of snakebite envenomation (SBE) in the world. Rural communities within India and other countries have long-held cultural beliefs surrounding snakes and SBE treatments, with snake statues present in numerous Hindu temples. While most cultural beliefs are well respected and do not affect anyone, some people worship live venomous snakes without any safety precautions. Moreover, they practice various inappropriate first aid and traditional treatments that exacerbate SBE-induced complications. We report an unusual case of SBE on the tongue of a patient who was bitten while worshipping Russell's viper following the advice of an astrologer based on the appearance of a snake in the patient's dream. Following the bite, the tongue was deeply incised by the priest as a first aid to mitigate SBE-induced complications. The patient suffered profuse bleeding and swelling of the tongue resulting in difficulties in intubating them. The patient regained consciousness after antivenom administration, intranasal ventilation, and blood removal from the mouth. The tongue underwent extensive surgery to restore movement and function. This report advises caution to those undertaking the extremely risky practice of worshipping live snakes and emphasises the urgent need to develop and enforce policies to mitigate such actions and educate rural communities.

Bilateral Simultaneous Optic Neuritis Following Envenomations by Indian Cobra and Common Krait.

In India, most snakebite envenomation (SBE) incidents are caused by the "Big Four" snakes which include Russell's viper, common krait, Indian cobra, and saw-scaled viper. Their common envenomation effects include neurotoxicity, myotoxicity, and coagulopathy. However, they also induce rare complications such as priapism, pseudoaneurysm, and sialolithiasis. Ocular manifestations such as optic neuritis develop rarely following envenomations by non-spitting snakes and they may cause temporary vision changes and blindness if untreated. While optic neuritis following Indian cobra envenomation has been reported previously, this was not encountered in victims of common kraits. Hence, for the first time, we report optic neuritis developed in a victim following envenomation by a common krait and compare its clinical features and diagnostic and therapeutic methods used with another case of optic neuritis in a victim of an Indian cobra bite. Both patients received antivenom treatment and made an initial recovery; however, optic neuritis developed several days later. The condition was diagnosed using ophthalmic examination together with computed tomography and/or magnetic resonance imaging methods. Due to very similar clinical features, both patients received intravenous corticosteroids which restored their vision and successfully treated optic neuritis. This case report suggests that the optic neuritis developed in a common krait envenomation is comparable to the one developed following a cobra bite, and therefore, the same diagnostic and therapeutic approaches can be used. This study also raises awareness of this rare complication and provides guidance for the diagnosis and treatment of SBE-induced optic neuritis.

Hirata's disease (insulin autoimmune syndrome) following envenomation by a common krait.

Snakebite envenomation is known to cause local as well as systemic haematological, myotoxic and neurological effects. Adverse effects on the endocrine system following envenomation are rarely reported. Hirata's disease, also known as insulin autoimmune syndrome (IAS) is a rare disorder that causes hypoglycaemia due to excessive production of insulin autoantibodies. This report describes a rare case of IAS which developed in a snakebite victim following envenomation by a common krait and antivenom treatment. The patient was initially treated with dextrose and corticosteroids, although plasmapheresis was required to reduce the concentration of insulin antibodies and normalise the patient's glucose level. The patient then made an uneventful recovery without permanent sequelae. This report demonstrates the impacts of envenomation by a common krait on developing Hirata's disease and creates awareness among clinicians who treat snakebite envenomation.

Development of Wunderlich syndrome following a Russell's viper bite.

Snakebite envenomation is a high priority neglected tropical disease that predominantly affects rural communities living in developing countries. Due to myriad of complications including coagulopathies, neurotoxicity, nephrotoxicity and local tissue destruction, treating snakebite victims is a major challenge for clinicians. Russell's viper (Daboia russelii) is one of the 'Big Four' venomous snakes in India, and it is responsible for the most snakebite-induced deaths and disabilities. Acute kidney injury occurs frequently following Russell's viper bites and it is a critical factor contributing to disabilities, deaths and excessive treatment costs. In addition to commonly observed envenomation effects, Russell's viper bites induce some rare complications such as priapism, sialolithiasis and splenic rupture. Here, we report a case of Wunderlich syndrome that developed in a 22-year-old male following a Russell's viper bite. The patient displayed severe coagulopathies, abdominal tenderness, and hypotension. Notably, a peri-nephric haematoma was identified through ultrasound and computerised tomographic imaging. The haemorrhage was successfully treated using angioembolisation, and the patient recovered without any difficulties. Although a clinical condition such as this is rare, it is important to create awareness among treating clinicians about its occurrence, diagnosis and clinical management.

Ultrasound-Guided Compression Method Effectively Counteracts Russell's Viper Bite-Induced Pseudoaneurysm.

Russell's viper (Daboia russelii), one of the 'Big Four' venomous snakes in India, is responsible for the majority of snakebite-induced deaths and permanent disabilities. Russell's viper bites are known to induce bleeding/clotting abnormalities, as well as myotoxic, nephrotoxic, cytotoxic and neurotoxic envenomation effects. In addition, they have been reported to induce rare envenomation effects such as priapism, sialolithiasis and splenic rupture. However, Russell's viper bite-induced pseudoaneurysm (PA) has not been previously reported. PA or false aneurysm is a rare phenomenon that occurs in arteries following traumatic injuries including some animal bites, and it can become a life-threatening condition if not treated promptly. Here, we document two clinical cases of Russell's viper bites where PA has developed, despite antivenom treatment. Notably, a non-surgical procedure, ultrasound-guided compression (USGC), either alone, or in combination with thrombin was effectively used in both the cases to treat the PA. Following this procedure and additional measures, the patients made complete recoveries without the recurrence of PA which were confirmed by subsequent examination and ultrasound scans. These data demonstrate the development of PA as a rare complication following Russell's viper bites and the effective use of a simple, non-surgical procedure, USGC for the successful treatment of PA. These results will create awareness among healthcare professionals on the development of PA and the use of USGC in snakebite victims following bites from Russell's vipers, as well as other viper bites.

Rapid development of a salivary calculus in submandibular gland and its potential causes in a young victim following Russell's viper bite.

Russell's viper bites are known to cause a range of haemotoxic, neurotoxic, myotoxic, cytotoxic and nephrotoxic complications. However, the impact of Russell's viper bites as well as bites from other venomous snakes on sialolithiasis has not been previously reported. Here, we present an interesting case where a Russell's viper bite induced the rapid development of a calculus in submandibular gland in a 10-year-old boy. Upon admission, the victim did not show any symptoms of swelling and/or pain around his oral cavity. He received antivenom treatment to normalise his coagulation parameters, however, on day three he developed swelling and extreme pain around his right mandibular region. An ultrasound investigation revealed the presence of a calculus in his submandibular gland, which was removed using a minor surgical procedure. The histopathological examination revealed this as a poorly calcified salivary calculus, which is composed of cell debris, mucopolysaccharides and lipids. The mechanisms behind its rapid development following a snakebite are unclear although this could be linked to excessive inflammation or modifications to the composition of saliva induced by venom toxins or other unknown factors. This report reveals an unusual complication induced by a Russell's viper bite and alerts clinicians who treat snakebites to be aware of such envenomation effects. Moreover, this will lead to novel research to explore the relationship between venom toxins and functions of salivary glands.

Oxygen Administration under Surgical Face Mask in COVID-19 Patients: A Game Changer.

COVID-19 is a multifaceted infectious disease. The development of hypoxemic respiratory failure is not uncommon during the course of illness in some of them. The objectives of the present study were to assess the effect of the addition of a surgical face mask while delivering oxygen via nasal cannula in hypoxemic COVID-19 patients and highlight on the advantages and patient's comforts. We prospectively assessed 30 consecutive conscious and hypoxemic COVID-19 patients, requiring oxygen via nasal cannula. The mean PaO2 without and with surgical face mask were 52 (+9) and 83 (-12) mm Hg respectively in the cohort, and the elevation in oxygen saturation was statistically significant (p <0.001). The present results encourage the delivery of oxygen under the surgical face mask in symptomatic COVID-19 patients, as it improves oxygen saturation and prevents aerosol dispersion with no change in PaCO2. The other advantages of this method are a reduction in the total requirement of oxygen per patient, better utilization of scarce resources, and lessening of the expenses incurred for oxygen. HOW TO CITE THIS ARTICLE: Senthilkumaran S, Koushik M, Meenakshisundaram R, Jena NN, Thirumalaikolundusubramanian P. Oxygen Administration under Surgical Face Mask in COVID-19 Patients: A Game Changer. Indian J Crit Care Med 2021;25(11):1286-1287.

Neutrophil Gelatinase-Associated Lipocalin Acts as a Robust Early Diagnostic Marker for Renal Replacement Therapy in Patients with Russell's Viper Bite-Induced Acute Kidney Injuries.

Snakebite-induced acute kidney injury (AKI) is frequently observed in patients following bites from vipers such as Russell's viper (Daboia russelii) in India. Currently, the levels of serum creatinine are mainly used as a marker to determine the necessity for renal replacement therapy (RRT) (haemodialysis) in severe cases of AKI. However, it takes up to 48 h to ascertain a distinct change in creatinine levels compared to its baseline level upon admission. The time lost between admission and the 48 h timepoint significantly affects the clinical management of snakebite victims. Moreover, early diagnosis of AKI and decision on the necessity for RRT in snakebite victims is critical in saving lives, reducing long-term complications, and minimising treatment costs arising from expensive haemodialysis. Neutrophil gelatinase-associated lipocalin (NGAL) has been recently studied as a robust early marker for AKI in non-snakebite patients. However, its suitability for clinical use in snakebite victims has not been rigorously established. Here, we demonstrate the clinical significance of plasma NGAL as a robust marker for RRT following AKI using a large cohort (309) of Russell's viper victims without any pre-existing health conditions. NGAL levels upon admission are positively correlated with creatinine levels at 48 h in different stages of AKI. Overall, NGAL acts as a robust early marker to ascertain the need for RRT following Russell's viper bites. The quantification of NGAL can be recommended as a routine test in hospitals that treat snakebites to decide on RRT at early time points instead of waiting for 48 h to confirm the increase in creatinine levels. The diagnostic use of NGAL in Russell's viper victims with pre-existing comorbidities and for other vipers should be evaluated in future studies.

Splenic rupture and subsequent splenectomy in a young healthy victim following Russell's viper bite.

Splenic rupture and/or splenectomy is/are not uncommon in clinical arena. Here we present this case of extensive haemorrhage-induced splenic rupture which resulted in splenectomy in a young healthy male (who did not have any previous medical conditions) following a Russell's viper bite. He developed upper abdominal and shoulder pain on his left side along with hypotension and reduced level of haemoglobin on the third day following bite despite antivenom treatment. Following confirmation of splenic rupture and haemoperitoneum by ultrasound and computed tomography scans, an emergency splenectomy was performed using laparotomy. Although Russell's viper bites are known to induce bleeding complications, splenic rupture due to haemorrhage in spleen has not been previously reported. Russell's viper venom toxins such as metalloproteases, serine proteases and phospholipase A2 might have affected the vascular permeability resulting in excessive bleeding and increased pressure in the spleen leading to rupture. Further investigations are required to underpin the impact of snake venom toxins on the architecture and functions of spleen. However, the clinicians who treat snakebites should be aware of this type of rare complications so as to provide appropriate management for such victims.

Visual Hallucinations After a Russell's Viper Bite.

Visual hallucinations (VHs) are extremely rare in snakebites. We report a case of Russell's viper bite in an otherwise healthy 55-y-old woman who presented to a hospital in south India with established clinical features of systemic and local envenomation, including coagulation failure, without any neurologic manifestations on admission. She reported simple VH on the third day, which abruptly stopped on the fifth day without any specific medications. Clinical, laboratory, imaging, and electrophysiological studies did not reveal any neuropsychiatric disorders. Including this case, only 5 cases of VH are documented in the literature, 2 following cobra and viper bites and 1 after a sea snake bite. Two cases were reported from Australia and 1 each from the United States, Iran, and India.