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1.  Haemodynamic patterns in patients with scorpion envenomation 
Heart  1998;79(5):485-489.
Objective—To study cardiovascular haemodynamics following scorpion envenomation.
Setting—Intensive care unit of a university hospital.
Patients—Eight patients with Indian red scorpion (Mesobuthus tamulus) stings.
Intervention—Captopril (6.25 to 12.5 mg orally) every 30 minutes until pulmonary oedema resolved.
Main outcome measures—Haemodynamic data obtained by pulmonary artery catheterisation.
Results—Two haemodynamic patterns were seen. There was a predominant vascular effect in one patient, with severe hypertension, tachycardia, increased systemic vascular resistance index (SVRI = 5893, and normal cardiac index (2.73 l/m2). A predominant myocardial effect with left ventricular dysfunction and normal right ventricular function was seen in the other seven patients, with tachycardia, pulmonary oedema, mild hypotension, reduced stroke volume (mean (SD), 25.9 (8.3) ml/m2), normal SVRI (1812 (831)−5), and increased pulmonary artery wedge pressure (PAWP = 25 (4.4) mm Hg). Following mild dehydration pulmonary oedema subsided (PAWP = 14 (8.5) mm Hg) in three of these patients, but hypovolaemic shock developed (right atrial pressure (RAP) = 1.3 (2.1) mm Hg); pulmonary oedema recurred with rehydration. One patient developed fatal cardiogenic shock with raised PAWP (27 mm Hg) and RAP (11 mm Hg), and vasodilatation (SVRI = 1129−5). Stroke volume (30.5 (8.7) ml/m2) and cardiac output (4.3 (1.5) l/m2) improved with resolution of pulmonary oedema (PAWP = 14.4 (4.2) mm Hg) following afterload reduction with captopril.
Conclusions—Mild envenomation causes severe vasoconstriction and hypertension. Severe envenomation produces predominant left ventricular dysfunction with normal systemic vascular resistance manifesting as pulmonary oedema or severe hypotension depending on the fluid balance. Shock due to biventricular dysfunction and vasodilatation occurs terminally.

 Keywords: scorpion sting;  myocarditis;  pulmonary oedema;  animal toxin
PMCID: PMC1728680  PMID: 9659196
2.  TNF-α Involvement in Insulin Resistance Induced by Experimental Scorpion Envenomation 
Scorpion venom induces systemic inflammation characterized by an increase in cytokine release and chemokine production. There have been few experimental studies assessing the effects of scorpion venom on adipose tissue function in vivo.
Methodology/Principal Findings
To study the adipose tissue inflammation (ATI) induced by Androctonus australis hector (Aah) venom and to assess possible mechanisms of ATI, mice (n = 6, aged 1 month) were injected with Aah (0.45 mg/kg), toxic fraction of Aah (FTox-G50; 0.2 mg/kg) or saline solution (control). Inflammatory responses were evaluated by ELISA and cell sorting analyses in adipose tissue 45 minutes and 24 hours after injection. Quantitative real-time PCR was used to assess the regulation of genes implicated in glucose uptake. The titers of selected inflammatory cytokines (IL-1β, IL-6 and TNF-α) were also determined in sera and in insulin target tissues. The serum concentration of IL-1β rose 45 minutes after envenomation and returned to basal level after 24 hours. The pathophysiological effects of the venom after 24 hours mainly involved M1-proinflammatory macrophage infiltration in adipose tissue combined with high titers of IL-1β, IL-6 and TNF-α. Indeed, TNF-α was strongly induced in both adipose tissue and skeletal muscle. We studied the effects of Aah venom on genes implicated in insulin-stimulated glucose uptake. Insulin induced a significant increase in the expression of the mRNAs for hexokinase 2 and phosphatidylinositol 3-kinase in both skeletal muscle and adipose tissue in control mice; this upregulation was completely abolished after 24 hours in mice envenomed with Aah or FTox-G50.
Our findings suggest that Aah venom induces insulin resistance by mechanisms involving TNF-α-dependent Map4k4 kinase activation in the adipose tissue.
Author Summary
Androctonus australis hector (Aah) is the scorpion most frequently causing serious human envenomation. In Algeria, Aah is responsible for approximately 50,000 cases of scorpion envenomation per year. The Aah sting causes multi-system failure that may be fatal; the manifestations include cardiopulmonary abnormalities, lung edema and inflammation. In addition, hyperglycemia and hyperinsulinemia have been described in scorpion-envenomed animals. The mechanisms causing systemic and local inflammation are poorly understood. Here, we report that Aah venom causes pronounced upregulation of TNF-α, IL1-β and IL-6 expression in the adipose tissue, exacerbating inflammation. As the inflammatory state intensifies, 24 hours after envenomation, TNF-α and other factors are upregulated, and Map4k4 expression increases, blunting the insulin response in adipocytes by decreasing Hexokinase 2 expression. Administration of TNF-α inhibitor following the envenomation reduces Map4k4 expression and restores glucose uptake in adipose tissue. These findings provide coherent evidence linking Aah venom-induced adipose tissue inflammation to insulin resistance. The value of TNF-α inhibitors as a treatment complementary to anti-scorpion venom immunotherapy should be evaluated clinically.
PMCID: PMC3398957  PMID: 22816003
3.  Clinical aspects of envenomation caused by Tityus obscurus (Gervais, 1843) in two distinct regions of Pará state, Brazilian Amazon basin: a prospective case series 
Scorpion envenomations are a major public health problem in Brazil, whose most dangerous cases are attributable to the genus Tityus. This study was designed to compare the clinical and demographic features of envenomations by Tityus obscurus in two areas of the state of Pará located in the Amazon basin.
Were compared demographic findings, local and systemic signs and symptoms of human envenomations caused by T. obscurus that occurred in western and eastern areas of the state.
Forty-eight patients with confirmed envenomation by T. obscurus were evaluated from January 2008 to July 2011. Most of them came from the eastern region, where male and female patients were present in similar numbers, while males predominated in the west. Median age groups were also similar in both areas. Most scorpion stings took place during the day and occurred significantly more frequently on the upper limbs. The time between the sting and admission to the health center was less than three hours in both areas. Most eastern patients had local manifestations while in the west, systemic manifestations predominated. Local symptoms were similar in both areas, but systemic signs and symptoms were more common in the west. Symptoms frequently observed at the sting site were local and radiating pain, paresthesia, edema, erythema, sweating, piloerection and burning. The systemic manifestations were significantly higher in patients from the west. Futhermore, neurological symptoms such as general paresthesia, ataxia, dysarthria, myoclonus, dysmetria, and electric shock-like sensations throughout the body were reported only by patients from the west.
The present study shows that two regions of Para state differ in the clinical manifestations and severity of confirmed envenomation by T. obscurus which suggests a toxicity variation resulting from the diversity of T. obscurus venom in different areas of the Brazilian Amazon basin, and that T. serrulatus antivenom can be successfully used against T. obscurus.
PMCID: PMC3923241  PMID: 24517181
Scorpionism; Tityus obscurus; Envenoming; Neurological symptoms; Brazilian Amazon
4.  Diagnostic utility of B-type natriuretic peptide in critically ill patients with pulmonary edema: a prospective cohort study 
Critical Care  2008;12(1):R3.
Distinguishing pulmonary edema due to acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS) from hydrostatic or cardiogenic edema is challenging in critically ill patients. B-type natriuretic peptide (BNP) can effectively identify congestive heart failure in the emergency room setting but, despite increasing use, its diagnostic utility has not been validated in the intensive care unit (ICU).
We performed a prospective, blinded cohort study in the medical and surgical ICUs at the University of Chicago Hospitals. Patients were eligible if they were admitted to the ICU with respiratory distress, bilateral pulmonary edema and a central venous catheter suggesting either high-pressure (cardiogenic) or low-pressure (ALI/ARDS) pulmonary edema. BNP levels were measured within 48 hours of ICU admission and development of pulmonary edema and onward up to three consecutive days. All levels were drawn simultaneously with the measurement of right atrial or pulmonary artery wedge pressure. The etiology of pulmonary edema – cardiogenic or ALI/ARDS – was determined by three intensivists blinded to BNP levels.
We enrolled a total of 54 patients (33 with ALI/ARDS and 21 with cardiogenic edema). BNP levels were lower in patients with ALI/ARDS than in those with cardiogenic edema (496 ± 439 versus 747 ± 476 pg/ml, P = 0.05). At an accepted cutoff of 100 pg/ml, specificity for the diagnosis of ALI/ARDS was high (95.2%) but sensitivity was poor (27.3%). Cutoffs at higher BNP levels improved sensitivity at considerable cost to specificity. Invasive measures of filling pressures correlated poorly with initial BNP levels and subsequent day BNP values fluctuated unpredictably and without correlation with hemodynamic changes and net fluid balance.
BNP levels drawn within 48 hours of admission to the ICU do not reliably distinguish ALI/ARDS from cardiogenic edema, do not correlate with invasive hemodynamic measurements, and do not track predictably with changes in volume status on consecutive daily measurements.
PMCID: PMC2374600  PMID: 18194554
5.  Efficacy and safety of scorpion antivenom plus prazosin compared with prazosin alone for venomous scorpion (Mesobuthus tamulus) sting: randomised open label clinical trial 
Objective Envenomation by Mesobuthus tamulus scorpion sting can result in serious cardiovascular effects. Scorpion antivenom is a specific treatment for scorpion sting. Evidence for the benefit of scorpion antivenom and its efficacy compared with that of commonly used vasodilators, such as prazosin, is scarce. We assessed the efficacy of prazosin combined with scorpion antivenom, compared with prazosin alone, in individuals with autonomic storm caused by scorpion sting.
Design Prospective, open label randomised controlled trial.
Setting General hospital inpatients (Bawaskar Hospital and Research Centre Mahad Dist-Raigad Maharashtra, India).
Participants Seventy patients with grade 2 scorpion envenomation, older than six months, with no cardiorespiratory or central nervous system abnormalities.
Intervention Scorpion antivenom plus prazosin (n=35) or prazosin alone (n=35) assigned by block randomisation. Treatment was not masked. Analysis was by intention to treat.
Main outcome measures The primary end point was the proportion of patients achieving resolution of the clinical syndrome (sweating, salivation, cool extremities, priapism, hypertension or hypotension, tachycardia) 10 hours after administration of study drugs. Secondary end points were time required for complete resolution of clinical syndrome, prevention of deterioration to higher grade, doses of prazosin required overall and within 10 hours, and adverse events. The study protocol was approved by the independent ethics committee of Mumbai.
Results Mean (SD) recovery times in hours for the prazosin plus scorpion antivenom group compared with the prazosin alone groups were: sweating 3 (1.1) v 6.6 (2.6); salivation 1.9 (0.9) v 3 (1.9); priapism 4.7 (1.5) v 9.4 (1.5). Mean (SD) doses of prazosin in the groups were 2 (2.3) and 4 (3.5), respectively. 32 patients (91.4%, 95% confidence interval 76.9% to 97.8%) in the prazosin plus antivenom group showed complete resolution of the clinical syndrome within 10 hours of administration of treatment compared with eight patients in the prazosin group (22.9%, 11.8% to 39.3%). Patients from the antivenom plus prazosin group recovered earlier (mean 8 hours, 95% CI 6.5 to 9.5) than those in the control group (17.7 hours, 15.4 to 19.9; mean difference −9.7 hours, −6.9 to −12.4). The number of patients whose condition deteriorated to a higher grade was similar in both groups (antivenom plus prazosin four of 35, prazosin alone five of 35). Hypotension was reported in fewer patients in the antivenom plus prazosin group (12 of 35, 34.3%) than in the prazosin group (19 of 35, 54.3%), but the difference was not statistically significant. No difference was noted in change in blood pressure and pulse rate over time between two groups.
Conclusion Recovery from scorpion sting is hastened by simultaneous administration of scorpion antivenom plus prazosin compared with prazosin alone.
Trial registration number CTRI/2010/091/000584 (Clinical Trials Registry India).
PMCID: PMC3016167  PMID: 21209062
6.  Echocardiography Guided Therapy for Myocarditis after Scorpion Sting Envenomation 
Objective: This study was to evaluate echocardiographic findings and its usefulness in clinical management of patients with scorpion sting envenomation.
Material and Methods: A total of 84 consecutive patients were prospectively studied. The data included demographics, at the time of presentation to the hospital, the clinical features, echocardiographic findings, admission to intensive care unit, use of inotropic medication, time to discharge, and mortality.
Results: Out of 84 patients studied 60 patients (71.4%) had echocardiographic evidence of myocarditis (LVEF <50%). Majority of patients had LVEF <40% (50 patients, 83.3%). Severe LV dysfunction (LVEF <30%) was noted in 20 patients (33.3%). No patient had significant valvular regurgitation. RV dysfunction was noted in half of the patients who had LV dysfunction. RV dysfunction was not seen in isolation. Twenty four patients without evidence of myocarditis on echocardiography were observed in general wards and were discharged in 24 to 48 hours of admission. Ten patients with mild LV dysfunction (LVEF 50-40%) and 20 patients with moderate LV dysfunction were observed in high dependency units with regular monitoring for 24 to 48 hours. Only 3 patients were put on inotropics support and others could be discharged in 72 to 96 hours. All the patients with severe LV dysfunction and moderate LV dysfunction with significant RV dysfunction were admitted in intensive care unit irrespective of symptoms (Total 30 patients). These patients were put on inotropics support. Among severe LV dysfunction group, 4 patients required ventilator support and 2 (2.3%) patients died with refractory shock and multi-organ failure. Tachycardia, muffled and or gallop heart sounds and hypertension didn’t predict presence of LV dysfunction. Persistent hypotension requiring inotropics support was a marker of severe LV dysfunction.
Conclusion: Echocardiography is a useful tool in emergency to assess LV function in patients with scorpion sting envenomation. It can guide therapy by identifying patients with severe LV dysfunction.
PMCID: PMC3919280  PMID: 24551651
Scorpion; Myocarditis; Envenomation; Echocardiography
7.  Outcome analysis and outcome predictors of traumatic head injury in childhood: Analysis of 454 observations 
To determine factors associated with poor outcome in children suffering traumatic head injury (HI).
Materials and Methods:
A retrospective study over an 8-year period including 454 children with traumatic HI admitted in the Intensive Care Unit of a university hospital (Sfax-Tunisia). Basic demographic, clinical, biological and radiological data were recorded on admission and during the ICU stay. Prognosis was defined according Glasgow outcome scale (GOS) performed after hospital discharge by ICU and pediatric physicians.
There were 313 male (68.9%) and 141 female patients. Mean age (±SD) was 7.2±3.8 years, the main cause of trauma was traffic accidents (69.4%). Mean Glasgow coma scale (GCS) score was 8±3, mean injury severity score (ISS) was 26.4±8.6, mean pediatric trauma score (PTS) was 4±2 and mean pediatric risk of mortality (PRISM) was 11.1±8. The GOS performed within a mean delay of 7 months after hospital discharge was as follow: 82 deaths (18.3%), 5 vegetative states (1.1%), 15 severe disabilities (3.3%), 71 moderate disabilities (15.6%) and 281 good recoveries (61.9%). Multivariate analysis showed that factors associated with poor outcome (death, vegetative state or severe disability) were: PRISM ≥24 (P=0.03; OR: 5.75); GCS ≤8 (P=0.04; OR:2.42); Cerebral edema (P=0.03; OR:2.23); lesion type VI according to Traumatic Coma Data Bank Classification (P=0.002; OR:55.95); Hypoxemia (P=0.02; OR:2.97) and sodium level >145 mmol/l (P=0.04; OR: 4.41).
A significant proportion of children admitted with HI were found to have moderate disability at follow-up. We think that improving prehospital care, establishing trauma centers and making efforts to prevent motor vehicle crashes should improve the prognosis of HI in children.
PMCID: PMC3132359  PMID: 21769206
Acute head injury; children; Glasgow coma scale score; intensive care unit; multivariate analysis; prognosis; trauma
8.  NT-proBNP in Myocarditis after a Scorpion Sting Envenomation 
Objective: This study was to evaluate the levels of NT-proBNP in patients with myocarditis which occurred after a scorpion sting envenomation.
Material and Methods: A total of 30 patients with scorpion sting envenomation and 21 patients with heart failure which was caused by cardiomyopathy, were prospectively studied. The data included the patient demographics, clinical features, echocardiography and the NT-proBNP levels.
Results: An echocardiographic evidence of myocarditis with a left ventricular ejection fraction of less than 50%, was found in 22 patients. In all the 22 patients, NT-proBNP was significantly elevated. The NT-proBNP levels were very high in the patients with severe LV dysfunction. However, it was in the normal range in the patients without an evidence of myocarditis. The elevated NT-proBNP levels were correlated with the LV dysfunction and myocarditis. When they were compared with the patients with heart failure which was caused by cardiomyopathy, the NTproBNP levels were found to be significantly more elevated in scorpion sting myocarditis.
Conclusions: The NT-proBNP levels were significantly elevated in myocarditis which occurred after a scorpion sting envenomation.
PMCID: PMC3576765  PMID: 23450100
Scorpion; Myocarditis; Envenomation; Echocardiography; NT-pro BNP
9.  Baseline characteristics and hospital mortality in the Acute Heart Failure Database (AHEAD) Main registry 
Critical Care  2011;15(6):R291.
The prognosis of patients hospitalized with acute heart failure (AHF) is poor and risk stratification may help clinicians guide care. The objectives of the Acute Heart Failure Database (AHEAD) registry are to assess patient characteristics, etiology, treatment and outcome of AHF.
The AHEAD main registry includes patients hospitalized for AHF in seven centers with a Catheterization Laboratory Service in the Czech Republic. The data were collected from September 2006 to October 2009. The inclusion criteria for the database adhere to the European guidelines for AHF (2005) and patients were systematically classified according to the basic syndromes, type and etiology of AHF.
Of 4,153 patients, 12.7% died during hospitalization. The median length of hospitalization was 7.1 days. Mean age of patients was 71.5 ± 12.4 years; men were younger (68.6 ± 12.4 years) compared to women (75.5 ± 11.5 years) (P < 0.001). De-novo heart failure was seen in 58.3% of the patients. According to the classification of heart failure syndromes, acute decompensated heart failure (ADHF) was reported in 55.3%, hypertensive AHF in 4.4%, pulmonary edema in 18.4%, cardiogenic shock in 14.7%, high output failure in 3.3%, and right heart failure in 3.8%. The mortality of cardiogenic shock was 62.7%, of right AHF 16.7%, of pulmonary edema 7.1%, of high output HF 6.1%, whereas the mortality of hypertensive AHF or ADHF was < 2.5%. According to multivariate analyses, low systolic blood pressure, low cholesterol level, hyponatremia, hyperkalemia, the use of inotropic agents and norepinephrine were predictive parameters for in-hospital mortality in patients without cardiogenic shock. Severe left ventricular dysfunction and renal insufficiency were predictive parameters for mortality in patients with cardiogenic shock. Invasive ventilation and age over 70 years were the most important predictive factors for mortality in both genders with or without cardiogenic shock.
The AHEAD Main registry provides up-to-date information on the etiology, treatment and hospital outcomes of patients hospitalized with AHF. The results highlight the highest risk patients.
PMCID: PMC3388663  PMID: 22152228
acute heart failure; AHEAD; in-hospital mortality; prognosis
10.  Comparative study between peripherally and centrally acting sublethal and lethal doses of Leiurus quinquestriatus scorpion venom in rabbits: The usefulness of the sodium channel blocker lidocaine 
Scorpion envenomation is common among desert dwellers, affecting several systems and resulting in multiple organ dysfunction (MOD) or failure (MOF), mainly due to their action on Na+ channels. Although scorpion venoms toxins do not pass the blood brain barrier, their CNS effects are prominent, occurring in conjunction with, or as an aftermath of peripheral actions of the venom.
To determine the ability of venom of the common scorpion Leiurus quinquestriatus (LQQ) to induce MOD or MOF when injected into rabbits in micro quantities centrally (intracerebroventricularly, i.c.v.) or macro amounts peripherally (s.c. or i.v.). Also, to assess if the Na+ channel blocker lidocaine can protect rabbits from the resultant manifestations.
Rabbits were injected with LQQ venom centrally or peripherally, in either sublethal or lethal doses, and MOD or MOF determined by assessing: cardiac output (CO), estimated hepatic blood flow (EHBF), biochemical parameters indicative of cardiac/hepatic/renal and pancreatic functions, blood pressure (BP), survival, lung/body index (LBI, indicative of pulmonary edema), and/or histological changes in hearts, lungs, livers plus kidneys. In pre-treatment experiments, lidocaine was injected 40 min before venom and protective ability examined.
LQQ venom in sublethal doses caused comparable significant reductions (vs control) in CO and EHBF when injected i.c.v. (2 μg kg−1) or s.c. (0.2 mg kg−1). Both routes caused gradual dose-related enhanced levels of creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, creatinine, glucose and amylase, indicating MOD. Also, characteristic venom-induced changes in BP were evident after lethal doses of venom i.v. (0.5 mg kg−1) or i.c.v. (3 μg kg−1). Histological changes in the organs plus LBI were comparable after i.c.v. and i.v. venom injection, with animals ultimately exhibiting MOF. Lidocaine (1 mg kg−1 i.v., then infusion 50 μg kg−1 min−1, 30 min before venom), protected the animals from MOF evoked by lethal doses of the venom (whether injected centrally or peripherally), as evidenced by the amelioration of the venom’s effects on blood pressure, LBI, survival and multiple organ histopathological manifestations.
LQQ venom, whether injected centrally or peripherally caused comparable systemic dose-dependent MOD or MOF, with the latter attenuated by the Na+ channel blocker lidocaine, indicating a role for Na+ channels.
PMCID: PMC3731021  PMID: 23964173
Leiurus quinquestriatus; Scorpion venom; Cardiac output; Estimated hepatic blood flow; Blood pressure; Lidocaine; Pulmonary index; Histopathological manifestations
11.  Mortality within hospital after resuscitation from ventricular fibrillation outside hospital. 
British Heart Journal  1992;67(4):334-338.
OBJECTIVE--To determine factors related to mortality within hospital after successful resuscitation from ventricular fibrillation outside hospital by a mobile coronary care unit manned by a physician. DESIGN--Retrospective review of records of patients resuscitated and admitted to hospital between 1 January 1966 and 31 December 1987. SETTING--Mobile coronary care unit, coronary care unit, and cardiology department. PATIENTS--281 patients (227 male), aged 14-82 (mean 58) successfully resuscitated from ventricular fibrillation outside hospital of whom 182 (65%) developed ventricular fibrillation before the arrival of the mobile coronary care unit. The aetiology of ventricular fibrillation was acute myocardial infarction in 194 patients (69%), ischaemic heart disease without infarction in 71 (25%), and other or unknown in 16 (6%). MAIN OUTCOME MEASURES--Death within hospital. RESULTS--There were 91 deaths in hospital (32%). Factors on univariate analysis significantly associated with increased mortality were patient age > or = 60 years, previous myocardial infarction or cerebrovascular disease, prior digoxin or diuretic treatment, collapse without prior chest pain or with pain lasting 30 minutes or less, defibrillation delayed by > or = 5 min, > or = four shocks required to correct ventricular fibrillation, left ventricular failure or pulmonary oedema and cardiogenic shock after successful defibrillation, and coma on admission to hospital. On multivariate analysis the most important factors (in rank order) were cardiogenic shock after defibrillation, coma on admission to hospital, age > or = 60 years and the requirement for four or more shocks to correct ventricular fibrillation. CONCLUSIONS--The in-hospital mortality of patients resuscitated from ventricular fibrillation outside hospital was related to patient characteristics before the cardiac arrest and to the immediate haemodynamic and neurological status after correction of ventricular fibrillation as well as to factors at the resuscitation itself. The in-hospital mortality of this study compares favourably with the results obtained by units staffed by paramedical workers and emergency medical technicians, although 35% (99/281) of the patients had ventricular fibrillation after the arrival of the mobile unit and defibrillation was thus rapid.
PMCID: PMC1024846  PMID: 1389711
12.  Clinical Course of Bark Scorpion Envenomation Managed Without Antivenom 
Journal of Medical Toxicology  2012;8(3):258-262.
Bark scorpion envenomation is potentially life threatening in children and traditionally treated with antivenom (AV). We sought to describe the clinical course, management, complications and outcome of children with severe scorpion envenomation treated with supportive care during a period when AV was unavailable. A retrospective chart review was performed, all children presenting to a referral hospital between September 1, 2004 and July 31, 2006 with severe scorpion envenomation not receiving AV, were included. A standardized data abstraction form was used to record time of symptom onset, time to healthcare facility (HCF), clinical findings, treatment, complications, and length of stay. Eighty-eight patients were included with mean age of 3.7 years (0.33–12). Mean time to symptom onset was 20 min (0–130) and mean time to HCF was 79 min (10–240). Incidence of clinical manifestations include: neuromuscular agitation, 100 %; opsoclonus, 97 %; hypersalivation, 81 %; tachycardia, 82 %; hypertension, 49 %; vomiting, 38 %; fever, 28 %; respiratory distress, 33 %; and hypoxia, 18 %. Complications included rhabdomyolysis in 18 (20 %) and aspiration in 12 (13 %) patients. Intubation was required in 24 % of patients. The most frequently used agents to control symptoms were benzodiazepines (98 %) followed by opioids (69 %). Intravenous fluids were given to 84 %. Mean length of stay was 29 h (range, 6–73 h). There were no deaths. In addition to the classic findings of neuromuscular hyperactivity, opsoclonus, and hypersalivation, a high incidence of hyperadrenergic findings and respiratory compromise are noted in this series. A significant number of patients required mechanical ventilation. Benzodiazpines and opioids were the most common medications used to control symptoms.
PMCID: PMC3550169  PMID: 22562239
Scorpion envenomation; Centruroides sculpturatus; Respiratory failure; Motor hyperactivity; Hyperadrenergic effects
13.  Scorpion Bite Induced Myocardial Damage and Pulmonary Edema 
A patient with electrocardiographic abnormalities after scorpion sting, simulating early myocardial infarction, is reported here. Pulmonary edema and congestive heart failure accompanied these electrocardiographic changes. The etiology of the cardiovascular manifestations in severe scorpion sting is related to the venom effects on the sympathetic nervous system and the adrenal secretion of catecholamines as well as to the toxic effects of the venom on the myocardium.
PMCID: PMC3385192  PMID: 22754636
Myocardial damage; pulmonary edema; scorpion bite
14.  Emerging options for the management of scorpion stings 
Scorpion stings are common in many tropical countries. Although most scorpion stings cause only localized pain without life-threatening envenoming, about one third of stings cause systemic envenoming which can result in death. Children are particularly sensitive to scorpion envenoming. The severity of scorpion stings is related to the presence of neurotoxins in the venom that cause a sudden release of neurotransmitters from the autonomic nervous system, predominantly sympathetic. There is also a strong inflammatory response that worsens symptoms, including those of a respiratory nature. Several vital functions may be directly affected, including the cardiovascular, respiratory, and neuromuscular systems. Hypertension is constant at the beginning of systemic envenoming and sometimes has a severe cardiac and respiratory impact. Although controversial, immunotherapy is the only etiological treatment. Administered early, it prevents many complications and improves the outcome. New antivenoms are highly purified immunoglobulin fragments, the efficacy and safety of which are excellent. As a consequence, adverse reactions to antivenoms are now very rare and usually mild, which should limit any reluctance regarding their routine use. Symptomatic treatment is still necessary to support immunotherapy, especially in cases of delayed arrival at hospital. A combination of both approaches should be considered, based on local resources and constraints.
PMCID: PMC3401053  PMID: 22826633
scorpion; envenoming; treatment; antivenom
15.  Central extracorporeal life support with left ventricular decompression for the treatment of refractory cardiogenic shock and lung failure 
The purpose of this prospective study was to evaluate the effects and functional outcome of central extracorporeal life support (ECLS) with left ventricular decompression for the treatment of refractory cardiogenic shock and lung failure.
Between August 2010 and August 2013, 12 consecutive patients (2 female) with a mean age of 31.6 ± 15.1 years received central ECLS with left ventricular decompression for the treatment of refractory cardiogenic shock and lung failure. Underlying disease was acute cardiac decompensation due to dilated cardiomyopathy (n = 3, 25%), coronary artery disease with acute myocardial infarction (AMI) (n = 3, 25%), and acute myocarditis (n = 6, 50%). We routinely implemented ECLS by cannulating the ascending aorta, right atrium and inserting a left ventricular decompression cannula vent via the right superior pulmonary vein.
All patients were successfully bridged to either recovery (n = 3, 25%), long-term biventricular support (n = 6, 50%) or cardiac transplantation (n = 3, 25%). Seven patients (58.3%) were discharged after a mean hospital stay of 42 ± 11.9 days. The overall survival from ECLS implantation to the end of the study was 58.3%. The cumulative ICU stay was 23.1 ± 9.6 days. The length of support was 8.0 ± 4.3 days (range 3-17 days).
We strongly recommend left ventricular decompression in refractory cardiogenic shock and lung failure to avoid pulmonary edema, left heart distension and facilitate myocardial recovery.
PMCID: PMC3974212  PMID: 24678718
Mechanical circulatory support; Cardiogenic shock; Lung failure; Extracorporeal life support
16.  Centruroides exilicauda Envenomation in Arizona 
Western Journal of Medicine  1984;141(5):634-637.
A retrospective survey of 1,135 telephone calls during 1980 and 1981, reporting scorpion envenomation to the Arizona Poison and Drug Information Center, was reviewed. Of these, 438 calls identified Centruroides exilicauda as the offending scorpion on the basis of description of the arthropod and consistency of physical findings and clinical course. Envenomation by C exilicauda occurred primarily in adults during the summer and early fall months of the year. Although most patients (92%) were treated at home with conservative therapy, 8% of patients either came to or were referred to a medical facility. Children younger than 5 years were frequently brought or were referred to either emergency care or inpatient hospital care. We conclude on the basis of this series that despite the historical reputation of lethality associated with envenomation by C exilicauda, most envenomations by this scorpion are relatively minor. The other important observation was that children younger than 5 years appear to be particularly prone to severe toxicity.
PMCID: PMC1011170  PMID: 6516334
17.  Acute respiratory failure in kidney transplant recipients: a multicenter study 
Critical Care  2011;15(2):R91.
Data on pulmonary complications in renal transplant recipients are scarce. The aim of this study was to evaluate acute respiratory failure (ARF) in renal transplant recipients.
We conducted a retrospective observational study in nine transplant centers of consecutive kidney transplant recipients admitted to the intensive care unit (ICU) for ARF from 2000 to 2008.
Of 6,819 kidney transplant recipients, 452 (6.6%) required ICU admission, including 200 admitted for ARF. Fifteen (7.5%) of these patients had combined kidney-pancreas transplantations. The most common causes of ARF were bacterial pneumonia (35.5%), cardiogenic pulmonary edema (24.5%) and extrapulmonary acute respiratory distress syndrome (ARDS) (15.5%). Pneumocystis pneumonia occurred in 11.5% of patients. Mechanical ventilation was used in 93 patients (46.5%), vasopressors were used in 82 patients (41%) and dialysis was administered in 104 patients (52%). Both the in-hospital and 90-day mortality rates were 22.5%. Among the 155 day 90 survivors, 115 patients (74.2%) were dialysis-free, including 75 patients (65.2%) who recovered prior renal function. Factors independently associated with in-hospital mortality were shock at admission (odds ratio (OR) 8.70, 95% confidence interval (95% CI) 3.25 to 23.29), opportunistic fungal infection (OR 7.08, 95% CI 2.32 to 21.60) and bacterial infection (OR 2.53, 95% CI 1.07 to 5.96). Five factors were independently associated with day 90 dialysis-free survival: renal Sequential Organ Failure Assessment (SOFA) score on day 1 (OR 0.68/SOFA point, 95% CI 0.52 to 0.88), bacterial infection (OR 0.43, 95% CI 0.21 to 0.90), three or four quadrants involved on chest X-ray (OR 0.44, 95% CI 0.21 to 0.91), time from hospital to ICU admission (OR 0.98/day, 95% CI 0.95 to 0.99) and oxygen flow at admission (OR 0.93/liter, 95% CI 0.86 to 0.99).
In kidney transplant recipients, ARF is associated with high mortality and graft loss rates. Increased Pneumocystis and bacterial prophylaxis might improve these outcomes. Early ICU admission might prevent graft loss.
PMCID: PMC3219351  PMID: 21385434
18.  Hemolytic uremic syndrome following Hemiscorpius lepturus (scorpion) sting 
Indian Journal of Nephrology  2008;18(4):166-168.
Scorpion envenomations are a public health problem in many countries. Scorpions are second only to snakes in causing human fatalities from envenomation. Species of scorpions capable of inflicting fatal stings are living in North and South Africa, the Middle East, India, America, Trinidad, and Tobago. Hemiscorpius lepturus (from the Hemiscorpiidae family) is the most medically important scorpion in Iran which accounts for 92% of all hospitalized scorpion sting cases. The venom from H. lepturus is primarily a cytotoxic agent and has hemolytic, nephrotoxic, and to some extent, hepatotoxic activities. We found a combination of microangiopatic hemolytic anemia, thrombocytopenia, and acute renal failure in a seven year-old female child who was referred to us with a 12 h history of bloody urine following a H. lepturus sting. Her blood smear showed fragmented erythrocytes and burr cells, leading us to a diagnosis of hemolytic uremic syndrome (HUS). This report highlights the importance of acceptable prophylaxis and therapeutic protocols for HUS in these patients.
PMCID: PMC2813541  PMID: 20142930
Hemolytic uremic syndrome; microangiopathic hemolytic anemia; scorpion sting
19.  Chronic obstructive pulmonary disease: hospital and intensive care unit outcomes in the Kingdom of Saudi Arabia 
There is little data surrounding the survival of patients with chronic obstructive pulmonary disease (COPD) who are admitted to the critical care unit with exacerbation of symptoms. We conducted a study to measure the in-hospital and intensive care unit (ICU) outcomes of patients admitted with COPD exacerbation, and identified the related prognostic factors.
We performed a retrospective cohort study of patients who were admitted to the adult ICU between January 2006 and July 2011 for COPD exacerbation in King Abdulaziz National Guard Hospital, Al-Hasa, Saudi Arabia.
During the study period, a total of 119 patients were admitted to the ICU with acute respiratory failure attributed to COPD exacerbation. The mean age was 72 ± 13 years, and 44 (37%) were females. The main cause of respiratory failure was infection, which occurred in 102 (86%) patients. Thirty-nine (33%) of the admitted patients were mechanically ventilated, and the median duration was 2.6 (1–42) days. The median lengths of the ICU and hospital stays were 3 (1–40) and 9 (2–43) days, respectively. The ICU mortality was 6%, and hospital mortality was 11%. Low Glasgow Coma Scale on admission, intubation, duration of mechanical ventilation, current smoking, tracheostomy, cardiopulmonary arrest, and the development of acute renal failure were associated with higher hospital mortality.
Early ICU and hospital mortality is low for COPD patients who have been admitted to the ICU with exacerbation. Low Glasgow Coma Scale scores on admission, intubation, prolonged use of mechanical ventilation, and the development of acute renal failure were identified as risk factors associated with increased hospital mortality.
PMCID: PMC3529632  PMID: 23269866
intensive care unit; chronic obstructive pulmonary disease; mortality rates; acute respiratory failure
20.  Phase II trial of isotonic fluid resuscitation in Kenyan children with severe malnutrition and hypovolaemia 
BMC Pediatrics  2010;10:71.
Children with severe malnutrition who develop shock have a high mortality. Contrary to contemporaneous paediatric practice, current guidelines recommend use of low dose hypotonic fluid resuscitation (half-strength Darrows/5% dextrose (HSD/5D). We evaluated the safety and efficacy of this guideline compared to resuscitation with a standard isotonic solution.
A Phase II randomised controlled, safety and efficacy trial in Kenyan children aged over 6 months with severe malnutrition and shock including children with severe dehydration/shock and presumptive septic shock (non-diarrhoeal shock). Eligible children were randomised to HSD/5D or Ringer's Lactate (RL). A maximum of two boluses of 15 ml/kg of HSD/5D were given over two hours (as recommended by guidelines) while those randomised to RL received 10 ml/kg aliquots half hourly (maximum 40 ml/kg). Primary endpoint was resolution of shock at 8 and 24 hours. Secondary outcomes included resolution of acidosis, adverse events and mortality.
61 children were enrolled: 41 had shock and severe dehydrating diarrhoea, 20 had presumptive septic shock; 69% had decompensated shock. By 8 hours response to volume resuscitation was poor with shock persisting in most children:-HSD/5D 15/22 (68%) and RL14/25 (52%), p = 0.39. Oliguria was more prevalent at 8 hours in the HSD/5D group, 9/22 (41%), compared to RL-3/25 (12%), p = 0.02. Mortality was high, HSD/5D-15/26(58%) and RL 13/29(45%); p = 0.42. Most deaths occurred within 48 hours of admission. Neither pulmonary oedema nor cardiogenic failure was detected.
Outcome was universally poor characterised by persistence of shock, oliguria and high case fatality. Isotonic fluid was associated with modest improvement in shock and survival when compared to HSD/5D but inconclusive due to the limitations of design and effectiveness of either resuscitation strategy. Although isotonic fluid resuscitation did not result in cardiogenic heart failure, as previously feared, we conclude that the modest volumes used and rate of infusion were insufficient to promptly correct shock. The adverse performance of the recommended fluid resuscitation guideline for severe malnutrition should prompt clinical investigation of isotonic fluids for resuscitation of compensated shock, defining rate and volumes required to inform future guidelines.
Trial Registration
The trial is registered as ISCRTN: 61146418
PMCID: PMC2973932  PMID: 20923577
21.  Scorpion Venom and the Inflammatory Response 
Mediators of Inflammation  2010;2010:903295.
Scorpion venoms consist of a complex of several toxins that exhibit a wide range of biological properties and actions, as well as chemical compositions, toxicity, and pharmacokinetic and pharmacodynamic characteristics. These venoms are associated with high morbility and mortality, especially among children. Victims of envenoming by a scorpion suffer a variety of pathologies, involving mainly both sympathetic and parasympathetic stimulation as well as central manifestations such as irritability, hyperthermia, vomiting, profuse salivation, tremor, and convulsion. The clinical signs and symptoms observed in humans and experimental animals are related with an excessive systemic host inflammatory response to stings and stings, respectively. Although the pathophysiology of envenomation is complex and not yet fully understood, venom and immune responses are known to trigger the release of inflammatory mediators that are largely mediated by cytokines. In models of severe systemic inflammation produced by injection of high doses of venom or venoms products, the increase in production of proinflammatory cytokines significantly contributes to immunological imbalance, multiple organ dysfunction and death. The cytokines initiate a cascade of events that lead to illness behaviors such as fever, anorexia, and also physiological events in the host such as activation of vasodilatation, hypotension, and increased of vessel permeability.
PMCID: PMC2838227  PMID: 20300540
22.  Motor aphasia: A rare complication of scorpion sting 
Scorpion sting is common in villages, and is an important public health problem in India. The clinical symptoms of envenomation by scorpion sting are by sympathetic and parasympathetic stimulation, causing a variety of symptoms. The leading causes of death are cardiac dysfunction and pulmonary edema. We present herein a case of scorpion sting in a 9-year-old boy who developed pulmonary edema and gradually developed cytotoxic cerebral edema with infarct leading to motor aphasia with upper motor neuron facial palsy.
PMCID: PMC3611920  PMID: 23560018
Cerebral infarct; motor aphasia; scorpion sting
23.  Post-traumatic pulmonary embolism in the intensive care unit 
Annals of Thoracic Medicine  2011;6(4):199-206.
To determine the predictive factors, clinical manifestations, and the outcome of patients with post-traumatic pulmonary embolism (PE) admitted in the intensive care unit (ICU).
During a four-year prospective study, a medical committee of six ICU physicians prospectively examined all available data for each trauma patient in order to classify patients according to the level of clinical suspicion of pulmonary thromboembolism. During the study period, all trauma patients admitted to our ICU were classified into two groups. The first group included all patients with confirmed PE; the second group included patients without clinical manifestations of PE. The diagnosis of PE was confirmed either by a high-probability ventilation/perfusion (V/Q) scan or by a spiral computed tomography (CT) scan showing one or more filling defects in the pulmonary artery or its branches.
During the study period, 1067 trauma patients were admitted in our ICU. The diagnosis of PE was confirmed in 34 patients (3.2%). The mean delay of development of PE was 11.3 ± 9.3 days. Eight patients (24%) developed this complication within five days of ICU admission. On the day of PE diagnosis, the clinical examination showed that 13 patients (38.2%) were hypotensive, 23 (67.7%) had systemic inflammatory response syndrome (SIRS), three (8.8%) had clinical manifestations of deep venous thrombosis (DVT), and 32 (94%) had respiratory distress requiring mechanical ventilation. In our study, intravenous unfractionated heparin was used in 32 cases (94%) and low molecular weight heparin was used in two cases (4%). The mean ICU stay was 31.6 ± 35.7 days and the mean hospital stay was 32.7 ± 35.3 days. The mortality rate in the ICU was 38.2% and the in-hospital mortality rate was 41%. The multivariate analysis showed that factors associated with poor prognosis in the ICU were the presence of circulatory failure (Shock) (Odds ratio (OR) = 9.96) and thrombocytopenia (OR = 32.5).Moreover, comparison between patients with and without PE showed that the predictive factors of PE were: Age > 40 years, a SAPS II score > 25, hypoxemia with PaO2/FiO2 < 200 mmHg, the presence of spine fracture, and the presence of meningeal hemorrhage.
Despite the high frequency of DVT in post-traumatic critically ill patients, symptomatic PE remains, although not frequently observed, because systematic screening is not performed. Factors associated with poor prognosis in the ICU are the presence of circulatory failure (shock) and thrombocytopenia. Predictive factors of PE are: Age > 40 years, a SAPS II score > 25, hypoxemia with PaO2/FiO2 < 200, the presence of a spine fracture, and the presence of meningeal hemorrhage. Prevention is highly warranted.
PMCID: PMC3183636  PMID: 21977064
Anticoagulation; ICU; predictive factors; pulmonary embolism; trauma patients
24.  Hemodynamic variables and mortality in cardiogenic shock: a retrospective cohort study 
Critical Care  2009;13(5):R157.
Despite the key role of hemodynamic goals, there are few data addressing the question as to which hemodynamic variables are associated with outcome or should be targeted in cardiogenic shock patients. The aim of this study was to investigate the association between hemodynamic variables and cardiogenic shock mortality.
Medical records and the patient data management system of a multidisciplinary intensive care unit (ICU) were reviewed for patients admitted because of cardiogenic shock. In all patients, the hourly variable time integral of hemodynamic variables during the first 24 hours after ICU admission was calculated. If hemodynamic variables were associated with 28-day mortality, the hourly variable time integral of drops below clinically relevant threshold levels was computed. Regression models and receiver operator characteristic analyses were calculated. All statistical models were adjusted for age, admission year, mean catecholamine doses and the Simplified Acute Physiology Score II (excluding hemodynamic counts) in order to account for the influence of age, changes in therapies during the observation period, the severity of cardiovascular failure and the severity of the underlying disease on 28-day mortality.
One-hundred and nineteen patients were included. Cardiac index (CI) (P = 0.01) and cardiac power index (CPI) (P = 0.03) were the only hemodynamic variables separately associated with mortality. The hourly time integral of CI drops <3, 2.75 (both P = 0.02) and 2.5 (P = 0.03) L/min/m2 was associated with death but not that of CI drops <2 L/min/m2 or lower thresholds (all P > 0.05). The hourly time integral of CPI drops <0.5-0.8 W/m2 (all P = 0.04) was associated with 28-day mortality but not that of CPI drops <0.4 W/m2 or lower thresholds (all P > 0.05).
During the first 24 hours after intensive care unit admission, CI and CPI are the most important hemodynamic variables separately associated with 28-day mortality in patients with cardiogenic shock. A CI of 3 L/min/m2 and a CPI of 0.8 W/m2 were most predictive of 28-day mortality. Since our results must be considered hypothesis-generating, randomized controlled trials are required to evaluate whether targeting these levels as early resuscitation endpoints can improve mortality in cardiogenic shock.
PMCID: PMC2784383  PMID: 19799772
25.  Enhanced External Counterpulsation (EECP) 
Executive Summary
To assess the effectiveness, and cost effectiveness of EECP in patients with severe anginal symptoms, secondary to chronic coronary disease, who are unresponsive to exhaustive pharmacotherapy and not candidates for surgical/percutaneous revascularization procedures (e.g., angioplasty, coronary bypass surgery).
To assess the effectiveness, and cost effectiveness of EECP in patients with heart failure.
Clinical Need
Angina is a clinical syndrome characterized by discomfort in the chest, jaw, shoulder, back or arm. Angina usually occurs in patients with coronary artery disease (CAD) involving ≥1 large epicardial artery. However it can also occur in people with valvular heart disease, hypertrophic cardiomyopathy, and uncontrolled hypertension.
Conventional approaches to restoring the balance between oxygen supply and demand focus on the disruption of the underlying disease through: drug therapy (β blockers, calcium channel blockers, nitrates, antiplatelet agents, ACE inhibitors, statins); life-style modifications (smoking cessation, weight loss); or revascularization techniques such as coronary artery bypass graft surgery (CABG) or percutaneous coronary interventions (PCI). (1) Limitations of each of these approaches include: adverse drug effects, procedure-related mortality and morbidity, restenosis after PCI, and time dependent graft attrition after CABG. Furthermore, an increasing number of patients are not appropriate candidates for standard revascularization options, due to co-morbid conditions (HF, peripheral vascular disease), poor distal coronary artery targets, and patient preference. The morbidity and mortality associated with repeat surgical revascularization procedures are significantly higher, and often excludes these patients from consideration for further revascularizations. (2)
Patients with CAD who have chronic ischemic symptoms that are unresponsive to both conventional medical therapy and revascularization techniques have refractory angina pectoris. It has been estimated that greater than 100,000 patients each year in the US may be diagnosed as having this condition. (3) Patients with refractory angina have marked limitation of ordinary physical activity or are unable to perform any ordinary physical activity without discomfort (CCS functional class III/IV). Also, there must be some objective evidence of ischemia as demonstrated by exercise treadmill testing, stress imaging studies or coronary physiologic studies. (1)
Dejongste et al. (4)estimated that the prevalence of chronic refractory angina is about 100,000 patients in the United States. This would correspond to approximately 3,800 (100,000 x 3.8% [Ontario is approximately 3.8% of the population of the United States]) patients in Ontario having chronic refractory angina.
Heart Failure
Heart failure results from any structural or functional cardiac disorder that impairs the ability of the heart to act as a pump.
A recent study (5) revealed 28,702 patients were hospitalized for first-time HF in Ontario between April 1994 and March 1997. Women comprised 51% of the cohort. Eighty-five percent were aged 65 years or older, and 58% were aged 75 years or older.
Patients with chronic HF experience shortness of breath, a limited capacity for exercise, high rates of hospitalization and rehospitalization, and die prematurely. (6) The New York Heart Association (NYHA) has provided a commonly used functional classification for the severity of HF (7):
Class I: No limitation of physical activity. No symptoms with ordinary exertion.
Class II: Slight limitations of physical activity. Ordinary activity causes symptoms.
Class III: Marked limitation of physical activity. Less than ordinary activity causes symptoms. Asymptomatic at rest.
Class IV: Inability to carry out any physical activity without discomfort. Symptoms at rest.
The National Heart, Lung, and Blood Institute (7) estimates that 35% of patients with HF are in functional NYHA class I; 35% are in class II; 25%, class III; and 5%, class IV. Surveys (8) suggest that from 5% to 15% of patients with HF have persistent severe symptoms, and that the remainder of patients with HF is evenly divided between those with mild and moderately severe symptoms.
To date, the diagnosis and management of chronic HF has concentrated on patients with the clinical syndrome of HF accompanied by severe left ventricular systolic dysfunction. Major changes in treatment have resulted from a better understanding of the pathophysiology of HF and the results of large clinical trials. Treatment for chronic HF includes lifestyle management, drugs, cardiac surgery, or implantable pacemakers and defibrillators. Despite pharmacologic advances, which include diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, spironolactone, and digoxin, many patients remain symptomatic on maximally tolerated doses. (6)
The Technology
Patients are typically treated by a trained technician in a medically supervised environment for 1 hour daily for a total of 35 hours over 7 weeks. The procedure involves sequential inflation and deflation of compressible cuffs wrapped around the patient’s calves, lower thighs and upper thighs. In addition to 3 sets of cuffs, the patient has finger plethysmogram and electrocardiogram (ECG) attachments that are connected to a control and display console.
External counterpulsation was used in the United States to treat cardiogenic shock after acute myocardial infarction. (9;10) More recently, an enhanced version namely “enhanced external counterpulsation” (EECP) was introduced as a noninvasive procedure for outpatient treatment of patients with severe, uncontrollable cardiac ischemia. EECP is said to increase coronary perfusion pressure and reduce the myocardial oxygen demand. Currently, EECP is not applicable for all patients with refractory angina pectoris. For example, many patients are considered ineligible for therapy due to co-morbidities, including those with severe pulmonary vascular disease, deep vein thrombosis, phlebitis and irregular heart rhythms, and heart failure. (1)
Very recently, investigation began into EECP as an adjunctive treatment for patients with HF. Anecdotal reports suggested that EECP may benefit patients with coronary disease and left ventricular dysfunction. The safety and effectiveness of EECP in patients with symptomatic heart failure and coronary disease and its role in patients with nonischemic heart failure secondary to LV dysfunction is unclear. Furthermore, the safety and effectiveness of EECP in the different stages of HF and whether it is only for patients who are refractive to pharmacotherapy is unknown.
2003 Health Technology Assessment by the Medical Advisory Secretariat
The Medical Advisory Secretariat health technology assessment (originally published in February 2003) reported on the effectiveness of EECP for patients with angina and HF. The report concluded that there was insufficient evidence to support the use of EECP in patients with refractory stable CCS III/IV angina as well as insufficient evidence to support the use of EECP in patients with HF.
Review Strategy
The aim of this literature review was to assess the effectiveness, safety, and cost effectiveness of EECP for the treatment of refractory stable CCS III/IV angina or HF.
The standard search strategy used by the Medical Advisory Secretariat was used. This included a search of all international health technology assessments as well as a search of the medical literature from December 2002 to March 2006.
A modification of the GRADE approach (11) was used to make judgments about the quality of evidence and strength of recommendations systematically and explicitly. GRADE provides a framework for structured reflection and can help to ensure that appropriate judgments are made. GRADE takes into account a study’s design, quality, consistency, and directness in judging the quality of evidence for each outcome. The balance between benefits and harms, quality of evidence, applicability, and the certainty of the baseline risks are considered in judgments about the strength of recommendations.
Summary of Findings
The Cochrane and INAHTA databases yielded 3 HTAs or systematic reviews on EECP treatment (Blue Cross Blue Shield Technology Evaluation Center [BCBS TEC], ECRI, and the Centers for Medicare and Medicaid Services [CMS]). A search of Medline and Embase December 2005 – March 2006 (after the literature search cutoff from the most recent HTA) was conducted using key words enhanced external counterpulsation, EECP, angina, myocardial ischemia, congestive heart failure. This search produced 1 study which met the inclusion criteria. This level 4a study was inferior in quality to the RCT which formed the basis of the 2003 Medical Advisory Secretariat recommendation.
BCBS reviewed the evidence through November 2005 to determine if EECP improves health outcomes for refractory chronic stable angina pectoris or chronic stable HF. (12) BCBS concluded that the available evidence is not sufficient to permit conclusions of the effect of EECP on health outcomes. Both controlled trials had methodologic flaws (MUST EECP and MUST EECP quality of life studies). The case series and observational studies for both indications while suggestive of a treatment benefit from EECP have shortcomings as well.
On March 20 2006, CMS posted their proposed coverage decision memorandum for external counterpulsation therapy. (13) Overall, CMS stated that the evidence is not adequate to conclude that external counterpulsation therapy is reasonable and necessary for:
Canadian Cardiovascular Society Classification (CCSC) II angina
Heart failure
NYHA class II/III stable HF symptoms with an EF≤35%
NYHA class II/III stable HF symptoms with an EF≤40%
NYHA class IV HF
Acute HF
Cardiogenic shock
Acute MI
In January 2005, ECRI (14) stated that there was insufficient evidence available to draw conclusions about the long-term effectiveness of EECP, with respect to morbidity, survival, or quality of life, for any coronary indication (refractory angina, congestive heart failure, cardiogenic shock and acute MI).
GRADE Quality of the Studies
According to the GRADE Working Group criteria, the quality of the trials was examined (Table 1). (11)
Quality refers to the criteria such as the adequacy of allocation concealment, blinding and followup.
Consistency refers to the similarity of estimates of effect across studies. If there is important unexplained inconsistency in the results, our confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect and the significance of the differences guide the decision about whether important inconsistency exists.
Directness refers to the extent to which the people interventions and outcome measures are similar to those of interest. For example, there may be uncertainty about the directness of the evidence if the people of interest are older, sicker or have more comorbidity than those in the studies.
As stated by the GRADE Working Group, the following definitions were used in grading the quality of the evidence. (11)
GRADE Quality of Studies
Economic Analysis - Literature Review
No economic analysis of EECP was identified in the published literature.
Estimated Prevalence of Angina in Ontario
3,800 patients with chronic refractory angina:
The number of patients with chronic refractory angina in the US is estimated to be approximately 100,000 (4), this corresponds to about 3,800 patients in Ontario (3.8% × 100,000) with refractory angina.
3,800 patients × $7,000 Cdn (approximate cost for a full course of therapy) ~ $26.6M Cdn.
Estimated Prevalence of Heart Failure in Ontario
23,700 patients EF ≤ 0.35:
This estimate is from an expert (personal communication) at the Institute for Clinical Evaluative Sciences (ICES), where they examined a sample of echocardiography studies drawn from a diagnostic lab in 2001. They found that the prevalence of EF ≤ 0.35 was 8.3%, and if generalized to all patients undergoing echocardiography, there would be 23,700 patients.
23,700 patients with EF ≤35% × $7,000 Cdn ~ $166 M Cdn.
There is insufficient evidence to support the effectiveness and safety of EECP treatment for patients with refractory stable CCS III-IV angina or HF.
As per the GRADE Working Group, overall recommendations consider 4 main factors. (11)
The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates and the relative value placed on the outcome.
The quality of the evidence.
Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise.
Uncertainty about the baseline risk for the population of interest.
The GRADE Working Group also recommends that incremental costs of healthcare alternatives should be considered explicitly alongside the expected health benefits and harms. (11) Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 2 is the overall trade-off between benefits and harms and incorporates any risk/uncertainty.
For angina and heart failure, the overall GRADE and strength of the recommendations is “weak” – the quality of the evidence is “low” (uncertainties due to methodological limitations in the study design in terms of study quality and directness), and the corresponding risk/uncertainty is increased due to a budget impact of approximately $26.6 M Cdn or $166 M Cdn respectively while the cost-effectiveness of EECP is unknown and difficult to estimate considering that there are no high quality studies of effectiveness.
Overall GRADE and Strength of Recommendation (Including Uncertainty)
PMCID: PMC3379533  PMID: 23074496

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