INSULIN ADMINISTRATION IN SEVERE SCORPION ENVENOMING

Original paper

INSULIN ADMINISTRATION IN SEVERE SCORPION ENVENOMING

B. YUGANDHAR , K. RADHA KRISHNA MURTHY , S. A. SATTAR

1 Department of Medicine, Kurnool Medical College & Government General Hospital, Kurnool, 518 002, India, 2 Department of Physiology, Seth G.S. Medical College & K.E.M. Hospital, Parel, Mumbai 400012, India.

ABSTRACT. The efficacy of insulin-glucose infusion in reversing myocardial damage, haemodynamic changes, peripheral circulatory failure, and pulmonary oedema was evaluated in 25 victims of venomous scorpion stings from the Rayalaseema region in the south of India. Myocardial damage with peripheral circulatory failure was seen in all scorpion sting victims. Ten of these victims also had pulmonary oedema. All the patients received continuous infusion of regular crystalline insulin at the rate of 0.3 U/g of glucose and glucose at the rate of 0.1 g/kg/h with supplementary potassium as needed, inotropic agents, oxygen, as well as maintenance of fluid, electrolytes and acid-base balance. Insulin-glucose infusion was associated with reversal of cardiovascular and haemodynamic changes, and pulmonary oedema in 24 of the 25 victims. One severely envenomed victim admitted 72 hours after the sting died. The scorpion envenoming syndrome with myocardial damage, cardiovascular disturbances, peripheral circulatory failure, pulmonary oedema, and many other clinical manifestations may cause multi-system organ failure (MSOF). It is characterised by a massive release of catecholamines, angiotensin II, glucagon, cortisol, and inhibition of insulin secretion. Under these altered conditions in the hormonal milieu, scorpion envenoming essentially results in a syndrome of fuel-energy deficits and an inability to use the existing metabolic substrates by vital organs, causing MSOF and death. Administration of insulin-glucose infusion to scorpion sting victims appears to be the physiological basis for the control of the metabolic response when that has become a determinant to survival.

KEY WORDS: scorpion, myocardial damage, pulmonary oedema, insulin-glucose infusion, peripheral circulatory failure.

INTRODUCTION

Death caused scorpion envenoming is common in tropical and subtropical countries (1,2,7,20,31,32,45). Stings by the Indian red scorpion of the Buthidae family (earlier called Buthus tamulus) result in a number of deaths (4-8,31,32,45-47). Treatment of human envenoming requires extensive knowledge of the clinical manifestations and mechanisms behind clinical signs and symptomatology (31,32,45-47). Besides the cardiovascular manifestations, pulmonary oedema is a frequent complication in many victims, especially in children. Many patients have died of pulmonary oedema (1-3,20). However, the mechanism/s of acute pulmonary oedema induced by scorpion venom is not completely understood. Cardiogenic and non-cardiogenic factors are involved in the pathogenesis of acute pulmonary oedema after scorpion stings (1-3,27,52). A review article on scorpion envenoming syndrome explained the pathophysiology involved in the cardiovascular system, pulmonary oedema, and the central nervous system (CNS) (20). However, the author has not considered the changes caused by scorpion envenoming in the hormonal environment, and consequently, the therapeutic role of insulin. The metabolic and electrocardiographic changes induced by experimental scorpion envenoming have been reversed by the administration of insulin alone (44) or insulin in combination with an alpha blocker and sodium bicarbonate (40).

Based on the reversal of these manifestations in our experimental scorpion envenoming, we have successfully demonstrated that insulin administration reversed the haemodynamic changes and pulmonary oedema in children stung by the scorpion Mesobuthus tamulus concanesis, Pocock in western Maharashtra (western India) (45).

The Rayalaseema region in the south of India is a high-risk area for venomous scorpion stings (Buthidae family) with high incidence of deaths (8,50). We have demonstrated here the efficacy of insulin-glucose infusion as a therapeutic treatment for envenomed adult victims.

PATIENTS AND METHODS

Twenty-five patients aged between 13 to 57 years with a history of scorpion envenomation were admitted to Medical Unit I of the Government General Hospital, at Kurnool Medical College, Kurnool, in the south India from December 1993 to November 1994.

The following tests were carried out as well as a routine clinical examination of all the scorpion sting victims: 1) Complete blood count: red blood cell count, white blood cell count, differential leukocyte count, and blood coagulation profile in suspected cases of disseminated intravascular coagulation; 2) Biochemical tests: blood glucose, blood urea, serum electrolytes, amylase, and glutamic oxalacetic transaminase (SGOT); 3) Urine tests: physical examination, albumin, sugar, ketone bodies, bile salts, bile pigments, and microscopic examination; 4) Electrocardiogram (ECG); 5) Chest X-ray.

The following treatment was administered to the victims of scorpion stings.

LOCAL TREATMENT. Injection of a local anaesthetic agent, such as 2% xylocaine (without adrenaline) at the sting site relieve pain. This was then repeated to relieve pain. Injection of tetanus toxoid was given as a prophylactic measure.

GENERAL PRINCIPLES. All patients suspected of scorpion envenoming were admitted for 48 to 72 hours for the monitoring of vital signs and treatment of abnormalities. All the patients received insulin-glucose infusion. Peripheral circulatory failure was managed by intravenous fluid administration.

INSULIN - GLUCOSE INFUSION. Plain insulin of 0.3 Units per gram glucose and glucose 0.1g/kg/h were given. This infusion was given continuously. Potassium chloride was given whenever necessary to prevent hypokalemia. The attending clinician was on the lookout for the earliest signs and symptoms of hypoglycemia so that it could be prevented and corrected.

Insulin-glucose infusion was discontinued after the clinical condition improved as indicated by a lowering in the elevated heart rate and respiratory rate, and attainment of normal central venous pressure and arterial blood pressure along with the disappearance of pulmonary oedema.

The following protocol was observed: 1) Seven Units of additional insulin for adsorption of insulin in the IV set; 2) Simultaneously, in a separate drip Dopamine and/or Dobutamine (5-7 µg/kg/min) in 5% dextrose to maintain blood pressure; 3) If the patient came in the "initial transient phase of hypertension", treatment of blood pressure with sublingual Nifedipine (5 mg for children and 10 mg for adults); 4) Maintenance of acid-base balance, adequate fluid load, electrolyte balance, renal output, and other necessary measures; 5) Nasal oxygen whenever necessary; and 6) Anxiolytic agents if necessary. The following drugs were not given: cardiac glycosides, atropine, corticosteroids, beta blockers, emetine hydrochloride (with local xylocaine injection), adrenaline (with local xylocaine injection), Angiotensin Converting Enyme (ACE) inhibitors.

RESULTS

Various general symptoms, physical signs, and ECG changes in scorpion sting victims are shown in Figure 1, Figure 2, Figure 3. The clinical presentation and outcome of the 25 scorpion sting victims treated with insulin-glucose infusion is shown in Table 1. The changes in the ECG before and after treatment with insulin-glucose infusion in two patients is shown in Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9.

FIGURE 1.
Symptoms of 25 patients envenomed by scorpions of the Buthidae family.

FIGURE 2.
Physical signs of 25 scorpion sting victims.

FIGURE 3.
Electrocardiographic changes seen in 25 scorpion sting victims.

FIGURE 4.
ECG changes seen in a 24-year-old adult male 5 h after scorpion sting. Sinus tachycardia (rate=120/min), ST segment depression in leads II, III and aVF, T inversion in aVL with tall T waves in leads II, III, aVF and V1-4.

FIGURE 5.
ECG taken 3 days after insulin-glucose infusion. Disappearance of sinus tachycardia (rate=75/min) and ST and T changes. Early re-polarization pattern in leads V3-6.

FIGURE 6.
ECG taken 8 days after the scorpion sting. Sinus rhythm and persistence of early re-polarization pattern in leads V3-6.

FIGURE 7.
ECG changes in a 25-year-old adult male 11 h after scorpion sting. Sinus tachycardia (rate=120/min), left axis deviation (-30º), QS complex in leads V1, and T wave inversion in aVL.

FIGURE 8.
ECG changes 24 h after insulin-glucose infusion. Sinus rhythm (rate=75/min), QRS axis at –30º, and T wave inversion in aVL.

FIGURE 9.
ECG changes 48 h after the scorpion sting. QRS axis at –30º and T wave inversion in aVL.

TABLE 1.
The clinical presentation and outcome of scorpion sting victims treated with insulin-glucose infusion.

The highest incidence of scorpion stings was in 13 to 30 year-old patients (18 of the 25 victims). The male female ratio is 2:1. In this study, 18 cases (72%) of scorpion stings occurred during the day at work, while 2 cases took place at night as the subjects were sleeping on the floor. The incidence of scorpion stings was high between July and December (22 of 25 the victims). Hyperglycemia (blood glucose more than 120 mg/dL ) in 10 (40%) cases, hyperkalemia (more than 5 mEq/L in 4 (16%) cases, an increase in SGOT in 12 cases (48%), and elevation of serum amylase in 5 victims (20%) were observed. No other significant change was observed in haematological, biochemical, and urine tests.

DISCUSSION

India harbours 99 species of scorpions belonging to all 6 families of scorpions; of these 45 species belong to the Buthidae family (55). Symptomatology in humans following scorpion stings is quite similar and may involve the CNS, the autonomous nervous system, the respiratory tract, the pancreas, and the cardiovascular system (54).

Experimental scorpion envenoming has been used by many authors to attempt to explain cardiovascular manifestations (8,10,12,14-21) (30,32,35,40,41,47,49,50,56). Myocardial damage was previously described in envenomed victims stung by different species of scorpions (10,11,14-21) (31,32,45,50,51,54,58). The patients in this study also showed clinical, laboratory, and ECG features compatible with myocardial damage.

Clinical reports of scorpion sting victims described different types of abnormal respiratory patterns that may cause death. Pulmonary oedema is a frequent complication in humans especially children stung by scorpions of several species (1-3,10,16-18,20). Forty percent of the scorpion sting victims in this study manifested pulmonary oedema. The pathogenesis of scorpion-venom induced pulmonary oedema has been reviewed by Ismail (19). Our views on the genesis of pulmonary oedema and its reversal by the administration of insulin-glucose infusion are shown below.

PULMONARY OEDEMA IN SCORPION ENVENOMING. Cardiogenic and non-cardiogenic factors are involved in the pathogenesis of acute pulmonary oedema following scorpion stings (1-3). Pulmonary oedema secondary to left-sided heart failure seldom occurs in the absence of previous lung injury. This may be explained by a simultaneous and localized increase in pulmonary vascular permeability with evidence of an increase in tracheobronchial aspirate/plasma protein concentration, light microscopic features of the lung compatible with the adult respiratory distress syndrome, electron microscopic findings compatible with acute lung injury, and increased alveolocapillary membrane permeability (1-3). Mathur et al. (24) have demonstrated non-cardiogenic pulmonary oedema without left ventricular dysfunction as shown by clinical, radiological, and echocardiographic findings. Rahav and Weiss (48) using scintigraphy described a scorpion sting victim with pulmonary oedema with a normal wedge pressure, indicating the possibility of capillary leak syndrome with adult respiratory distress syndrome (ARDS). The clinical presentation of ARDS is essentially a constellation of symptoms and findings that would be expected to result from hypoxemia and pulmonary oedema initially. ARDS is a pulmonary manifestation of pansystemic injury and MSOF (52).

The presence of MSOF can be inferred by the appearance of concurrent and otherwise unexplained pulmonary, CNS, renal, hepatic, and heamatologic functional abnormalities in a clinical setting involving either infectious or non-infectious inflammation or tissue injury. ARDS is commonly diagnosed first because oedematous lung injury has immediate life-threatening clinical manifestations. In contrast, other organs may maintain functional integrity despite extravasation of oedematous fluid. Some of the subtle manifestations of extra pulmonary dysfunction include altered mental condition, hyperglycemia, ongoing volume requirements to maintain blood pressure, diminished urine output, thrombocytopenia, prolongation of prothrombin time, and heme positive stools. These problems may be so overshadowed by respiratory failure as to attract little attention (52).

Scorpion venom may cause stimulation of the CNS, the autonomous nervous system, cardiovascular, electrocardiographic, haematologic, and hormonal disturbances (4,5,21,28-34) (35-42) (43-47,49), along with pulmonary (cardiac and non-cardiogenic) oedema, as demonstrated by earlier researchers (1-3,6,7,9-11) (15-20,22-24) (45,48-51,54,58).

Freire-Maia and De Matos (11) showed the efficacy of heparin or BN 52021, a PAF antagonist in the prevention of acute pulmonary oedema by Tityus serrulatus venom in rats. However, heparin, which decreased pulmonary vascular permeability and prevented pulmonary oedema, failed to prevent pulmonary oedema formation following envenoming by Mesobuthus tamulus concanesis, Pocock in rats (49).

The chemical composition and the functional activity of the surfactant are altered in ARDS (52). Surfactant deficiency could be the final common pathway in the pathogenesis of ARDS (27). The loss or insufficient quantity of surfactant may explain the pulmonary oedema associated with scorpion envenoming, since surfactant is preferentially formed from glucose and glycogen rather than from glycerol, and insulin is required for its formation (23). Forty percent of our patients had pulmonary oedema. All the patients had circulatory failure, myocardial damage, and many other clinical manifestations. All these scorpion sting victims, with one exception, recovered after the administration of insulin-glucose infusion. None of the victims received ventilation support.

Insulin-glucose infusion and conventional therapy were given to patients with both ARDS and MSOF following septic shock syndrome (other than scorpion envenoming syndrome) (46). Blood gases improved between 2 and 8 hours after insulin-glucose infusion resulting in normal biochemical profile, radiological clearance of the lungs, and clinical improvement (46). If surfactant damage or insufficiency is truly the final common pathway, and thus, a key step in the development of pulmonary oedema in scorpion envenoming and ARDS, therapeutic opportunities of surfactant replacement by insulin-glucose administration offer exciting, cheap, and effective possibilities for early intervention.

RATIONALE FOR INSULIN THERAPY IN SCORPION ENVENOMING. Scorpion envenoming causes the release of massive amounts of catecholamines (epinephrine and nor-epinephrine) (3) and other counter-regulatory hormones (glucagon and cortisol) with suppressed insulin secretion. Under these conditions, the metabolism of carbohydrate, protein, and fat is directed towards catabolism. Lipolysis results in increased FFA levels that are arrhythmogenic in nature and inhibits Na - K ATPase activity. Insulin is the only major hormone that tends to suppress the mobilization of fatty acids from adipose tissue. This effect occurs at insulin concentrations below those needed for glucose uptake in most tissues. In addition, the effect of fatty acid mobilization is immediate, faster than the effect on plasma glucose levels. Insulin allows the incorporation of fatty acids into triglycerides in the liver and in adipose tissues. In addition, infusion of glucose along with insulin will suppress fat mobilization by promoting re-esterification.

Insulin promotes glycogen deposition and inhibits glycogen degradation. Insulin counteracts the effects of catecholemines favouring glucose uptake and inhibiting gluconeogenesis by the suppression of the flow of substrates to the liver. It also inhibits lipolysis in adipose tissues, reducing the flow of free fatty acids to the liver, thus removing a trigger for gluconeogenesis. Glycogen availability may be an important independent determinant of cardiac function. Elevated glycogen content in the heart partially protects the mechanical deterioration in anoxia.

Cardiac and liver glycogen content was found to be reduced after envenomation by the scorpion Mesobuthus tamulus concanesis, Pocock (4,5,40,44). Insulin administration resulted in a massive increase in glycogen content in the liver, skeletal and cardiac muscles, and lipogenesis in the scorpion envenomed animals (40,44).

Insulin assists in the recovery of myocardial contractility after ischaemic arrest and increases cardiac output (26). Insulin also assists glucose transport and can accelerate ATP production in ischaemic areas (26). Insulin stimulates sarcolemmal Na - K ATPase activity (13), inhibits Ca ATPase activity, and stabilizes lysosomal membranes (13).

The Na - K pump has a key function in the exchange of substances between the cell and its surroundings, in transepithelial transport, and in transmission of information (53). Three isoforms of the Na - K ATPase alpha subunit have been identified. The functional implications of having three isoforms of the enzyme are still unknown. The only observation that points towards a special function is that the affinity of the alpha 2 isoform for Na from muscles and adipocytes is increased by insulin (53).

The activity of Na - K pump in the intact membrane is determined by a combined effect of the cytoplasmic and extracellular Na to K concentration ratios and other factors. Insulin, epinephrine, and nor-epinephrine have a stimulating effect on the pump (53). The alterations in the cardiac sarcolemmal (28) and red blood cell Na - K ATPase activity and reduction in insulin secretion (29,40,42,44,47) were shown in scorpion envenoming.

Recently, both in vivo and in vitro studies have shown that resolution of oedema from the air spaces of the lungs depended on an active sodium transport pump that removed oedema fluid, even in the face of a rising alveolar oedema protein concentration in excess of plasma protein concentration (25).

In our hands, the administration of insulin alone (44) or insulin and alpha blocker (40) successfully reversed the metabolic as well as ECG changes in experimental scorpion envenoming. Insulin along with alpha blocker produced little more glycogenesis and lipogenesis and reversed the rise in plasma angiotensin II levels (36,40,44) than insulin alone. However, the alpha blockers are known to stimulate the gastric acid secretion, and this may, in turn, aggravate the existing sub-clinical or clinical acute pancreatitis (43), known to occur in some patients, into a fully blownup fulminating acute pancreatitis in some scorpion sting victims. In this study, mild epigastric pain was the complaint of 9 (36%) patients, and elevation of serum amylase levels was seen in 5 (20%) of these victims.

If stimulation of nerves to the pancreas inhibits insulin secretion via the release of catecholamines (via the alpha adrenoceptor stimulation to pancreas), then it is logical to convert the inhibitory response to an excitatory response by using alpha blocking drugs (13). If alpha blockers are acting by release of insulin, we can very well administer insulin instead of alpha blockade-dependent insulin release to reverse the metabolic, electrocardiographic, haemodynamic changes, non-cardiogenic respiratory pulmonary oedema (ARDS-like syndrome), and many other changes induced by scorpion venom. Prazosin (alpha adrenergic antagonist) is found to enhance insulin secretion in scorpion sting victims with suppressed insulin secretion (prior to prazosin treatment) (6,7).

Alpha blockers can prevent the actions caused by released catecholamines, preventing further damage. Alpha blockers can not reverse the tissue damage that has already been caused by catecholamines. Thus, insulin remains the only choice as the physiological antagonist to the actions of catecholamines.

In another study, 105 scorpion sting victims were treated with insulin-glucose infusion (58). Seven of the 8 scorpion sting victims with hypertension, myocarditis with or without disturbances of rate or rhythm, 80 of the 81 patients with myocarditis and peripheral circulatory failure, 14 of the 16 scorpion sting victims with pulmonary oedema, myocarditis and peripheral circulatory failure, have completely recovered after insulin-glucose infusion (58). Three of these 105 victims died possibly because they sought treatment at least 48 hours after scorpion sting (58).

Appropriate serotherapy with the appropriate antivenom doses is unsurpassed in reducing morbidity and mortality caused by venomous scorpion stings (20). The administration of antivenom under laboratory conditions effectively neutralised, prevented, and reversed cardiovascular, haemodynamic, metabolic, and electrocardiographic changes in experimental animals and patients (57) stung by the Indian red scorpion of the Buthidae family (21,47). Forty-five medically important species of scorpion belonging to the Buthidae family are distributed throughout India (55). The Rayalaseema region in the south of India, from where this study is reported, has more than 6 species of scorpions of the Buthidae family (55). In the absence of species-specific effective scorpion antivenom, comparisons can not be made with studies that used serotherapy from other countries. The consequences of the scorpion envenoming syndrome have been underestimated, never fully portrayed in health statistics, and treated using old-fashioned and mostly ineffective procedures. The mortality rate of patients stung by scorpions of the Buthidae family from many places in India with pulmonary oedema is around 40% and without pulmonary oedema around 30%.

It can be concluded that, the administration of insulin-glucose infusion should be recommended as the first choice therapy given as soon as possible, immediately after hospitalization in intensive care units, to envenomed patients whose clinical picture is dominated by pulmonary oedema, cardiovascular, and many other clinical manifestations. We have highlighted the role of insulin-glucose infusion in the treatment of scorpion envenoming. This is an entirely new approach, which requires dissemination and controlled randomized confirmatory studies.

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Received 30 January 1998

Accepted 25 June 1998

CORRESPONDENCE TO:

K. RADHA KRISHNA MURTHY, D. Sc., M.D., M.A.M.S., Professor of Physiology, Seth G.S. Medical College, & K.E.M. Hospital, Parel, Mumbai 400012, India.

Publication Dates

• Publication in this collection
  17 Sept 1999
• Date of issue
  1999

History

• Received
  30 Jan 1998
• Accepted
  25 June 1998