No

Introduction

Pellagra is a nutritional disorder due to an insufficiency in vitamin B₃ also called vitamin PP (‘Pellagra preventing’). The disease was characterized by the following ‘3 D’s’: ‘Dermatitis’, ‘Dementia’ and ‘Diarrhoea’. When it is misdiagnosed, it can lead to the fourth ‘D’ which is ‘Death’.¹ It was very common in past centuries, particularly in populations that had an exclusively maize diet. Nowadays, this diet problem is rare in developed countries, so the disease is less frequent. However, many recent studies suggest that the disease has not been eradicated and can be under-diagnosed. Alcohol, drugs and malabsorption seem to be the new aetiologies of the disease. So, it is important to recognize the ‘3 D’s’ triad in such situations to avoid fatalities.

Observation

A 61-year-old patient presented to the Internal Medicine Department with an 8-month history of deterioration in her general state. She had a medical history of Epilepsy treated by Phenobarbital since she was 16.

Review of systems revealed gastrointestinal symptomatology consisting of intermittent diarrhoea (6-7 watery stools a day without blood), dysphagia and diffuse abdominal pain. The patient also reported a skin photosensitive eruption affecting her hands and feet.

Physical examination showed a listless patient with a low Body Mass Index (17 kg/m²).

On dermatological examination, symmetric, well-defined, brown-coloured and scaly eruption was observed on the dorsa of her feet (Picture 1) and hands (Picture 2). The mucous examination showed a commissural Cheilitis and Glossitis.

Picture 1: Brown well-defined patches on feet.

Picture 2: Brown pigmentation and scales of hands.

Picture 3: Hands aspect after treatment.

The nervous system examination revealed a pyramidal and cerebellar syndrome. The response to neurocognitive tests was altered suggesting Dementia.

The rest of physical examination was normal. In particular, there were neither peripheral lymph nodes, nor spleen or liver enlargements, nor abdominal mass.

The laboratory tests (glucose, calcaemia, creatinine, liver function tests, urine analysis, haemoglobin, hematocrit, sedimentation rate, C-reactive protein and protein electrophoresis) were within normal limits.

Oesogastroduodenal endoscopy was normal. The cranial, thoracic and abdominal CT scans were normal.

The diagnosis of Pellagra was made on dermatological, abdominal and neurological signs. The patient was treated by Niacin (1000 mg/day) and multivitamin complex. Phenobarbital was discontinued and switched to Clobazam. The patient’s symptoms started to improve quickly. Ten days after the treatment began the skin lesions (Picture 3) and gastrointestinal signs completely disappeared.

Discussion

Pellagra was diagnosed clinically in our patient based on the skin aspects. The skin lesions have been described since 1771 by Frapolli whose name was given to the disease: Pellagra which means rough skin in Italian.¹ The typical lesions consist of a brown pigmentation and scales with a photosensitive distribution and well-defined borders as seen in our patient. The face, the neck and the dorsa of the hands are the preferential locations.² The skin lesions are not always found, and cases of Pellagra Sine Pellagra have been described.³ The extra-cutaneous manifestations are less specific, but their association with pellagrous skin lesions are sufficient to reach a diagnosis. The neurological involvement is classically a Dementia syndrome, but ‘Pellagrous Encephalopathy’ can also consist of delirium, insomnia, depression, cerebellar and extrapyramidal syndrome.⁴ The gastrointestinal signs are non-specific; they can be Glossitis, dysphagia, nausea, vomiting and abdominal pain. An intractable diarrhoea may occur in advanced stages of disease and can quickly lead to death.⁵

In 1929, Goldberger attributed such clinical manifestations to a Niacin (vitamin B₃ or PP) deficiency. Niacin is a precursor for two important coenzymes namely ‘Nicotinamide Adenine Dinucleotide (NAD)’ and ‘NAD-Phosphate’ which are essential for many oxidative reactions. This probably explains why Pellagra affects tissues with a high rate of cell turnover such as the skin and digestive tract.⁴

Niacin can be directly absorbed by the gastrointestinal tract or synthesized from Tryptophan.

Primary Pellagra occurs when the diet is deficient in Niacin or Tryptophan as in poor populations with an exclusive maize diet (which contain Niacin but in an indigestible form).

Despite sufficient dietary Niacin, Secondary Pellagra may be caused by a problem in Niacin absorption or metabolism. Many causes of Secondary Pellagra were identified as alcohol, intestinal malabsorption, carcinoid tumours, Hartnup’s Syndrome, Anorexia Nervosa and drugs (Table 1).⁵ Our patient did not consume alcohol and had no biological signs of malabsorption, but she was taking Phenobarbital for about 45 years. In the English literature, we found only two cases of Phenobarbital-induced Pellagra, and with a fatality in one case.^{6, 7} The underlying mechanism of Pellagra caused by Phenobarbital, or other antiepileptic drugs, is an alteration in Niacinamide synthesis due to an enzymatic induction.⁵

Table 1: List of drugs predisposing to Pellagra.

The treatment is first based on correction of predisposing factors. In our patient, it consisted of using another antiepileptic drug instead of Phenobarbital. Second-line treatment is a vitamin therapy based on Niacin. There is no consensus on the doses, form and duration of the treatment, but the minimal dose is 300 mg of Niacin/day. A multivitamin complex containing other B-vitamins is often necessary because of the frequency of other deficits in such patients.² With treatment, the skin lesions and gastrointestinal symptoms generally disappear within a few hours or days, as in the case of our patient, and it is a good argument for a retrospective diagnosis of pellagra.¹ Testing for Niacin levels or urinary metabolites is not frequently available and it’s not necessary for the diagnosis.

Conclusion

We described a typical case of Pellagra in which the ‘3 D’s’ were present. In such a case, we should begin the treatment before the results of the laboratory investigations are known. The improvement of all symptoms within a few days is sufficient to confirm the diagnosis. However, the ‘3 D’s’ triad is not always present, and the clinician should consider the diagnosis in face of unexplained abdominal or neurological signs in certain patient groups.

Introduction

Dilated cardiomyopathy (DCM) is a cardiac muscle disease, characterized by dilatation and impaired contraction of the left ventricle or both ventricles, and leads to progressive heart failure and sudden or heart failure-related death [1]. The life expectancy is limited and varies according to the underlying etiology with a median survival time of about 5 years after diagnosis [2]. Although the pathogenesis of this disease has been extensively studied for decades, it remains ambiguous. Currently, myocarditis, immunological abnormalities, toxic myocardial damage, and persistent cardio-tropic viral infection are all assumed to be causes of DCM [3]. Dilated cardiomyopathy occurring in families, or the familial dilated cardiomyopathy (FDC) may occur in 25% to 35% of DCM cases, implicating a genetic contribution to the etiology [4-7].  More than 30 susceptibility genes have been shown to be associated with an increased risk of developing a DCM. Here we report three strange cases of FDC accompanied by hearing loss and rapid progressive course in brothers from Sichuan Province of China. The presentation of the family was really rare and it is anticipated that more susceptibility genes may be discovered.

Case report

The patient was a boy from Sichuan Province, and had lost his hearing when he was five years old. At the age of eight, the boy presented with cough and acute onset breathlessness. On examination, he had blood pressure (BP) of 90/60mmHg, heart rate (HR) 105/min, raised jugular venous pressure (JVP), crackles over the lung bases and a pansystolic murmur at the apex. A huge cardiomegaly was seen on chest X-ray (CXR), and the cardiothoracic ratio (CT ratio) was 0.721. ECG revealed primary atrioventricular block and left ventricular hypertrophy (LVH). Echocardiography (Echo) showed enlargement of both ventricles of the heart, a decreased left ventricular ejection fraction (LVEF), and severe mitral regurgitation (MR). The patient was treated in line with congestive cardiac failure (CCF). However, he died three months after the acute onset of breathlessness.

Surprisingly, the progression was nearly the same as two of his older brothers. Both of them also lost hearings at the age of five. Then presented with acute onset breathlessness and they were diagnosed with DCM aged seven to eight years. They also died three months later after the acute onset of breathlessness. Because of the terrible experience of his older brothers, the boys’ parents took him to hospital every year to be examined. ECG and Echo images were normal 6 months before the onset of breathlessness. Moreover, the boy had no symptoms 1 month before his presentation.

Discussion

The definition of FDC is clinically based on manifestation with at least two affected members from the same family [5]. The most common mode of inheritance is the autosomal dominant type, while X-linked, autosomal recessive and mitochondrial forms are less common [8, 9]. Although most people affected die in early adulthood, the age of onset, rate of progression, disease complications, as well as overall prognosis and outcome vary within families [5, 10]. Nevertheless, the age of onsets in this family were similar and with a rapid progressive course. All of the sons in the family suffered from DCM as well as hearing loss. The manifestation of the brothers haven’t been reported before. We traced back three generations of this family finding no other affected members.  As all the patients were male, we speculated that the possible mode of inheritance in this family is X-linked. Regrettably, the parents had no daughters and we were not able to investigate the possible association between gender and FDC of this kind. Because of the rapid progressive course, we hypothesize that autoimmune abnormalities might be the pathogenic factors for this disease, but we do not have any solid evidence yet. Fortunately, we were able to get the blood samples from the patient and the relatives. Further studies are needed to explore new susceptibility genes as well as the molecular mechanisms that are involved in the disease.

INTRODUCTION

Achalasia is a rare oesophageal motility disorder, typically presenting with symptoms of dysphagia, regurgitation of food and retrosternal chest pain made worse on eating. The annual incidence in the UK, Ireland and USA is between 0.5 to 1.2 per 100,000¹ and seems to affect both sexes and all races equally.

The aetiology of achalasia remains largely unknown. However, suggested influences include a genetic predisposition, infection and autoimmunity^2,3. The changes responsible for achalasia include a combination of both poor oesophageal contractility and impairment of relaxation of the lower oesophageal sphincter resulting in oesophageal distension and symptoms described above. Reaching a diagnosis relies on oesophageal manometry in addition to barium swallow and oesophagogastroduodenoscopy (OGD).

The condition was first described by a British physician in 1674, Sir Thomas Willis, and treated with dilatation using a sponge attached to a whale bone⁴. It was not until many years later in 1913 that a German surgeon, Heller, performed the first cardiomyotomy⁵. The optimal treatment for achalasia remains controversial with treatment largely dependent on the preference of the physician. Cases are few and far between and therefore large studies reviewing the optimal treatments are limited.

This review aims to identify and collaborate relevant literature detailing the management options available to treat achalasia.

METHODS

An extensive literature search was performed using Ovid MEDLINE, Cochrane library and PubMed databases for relevant articles relating to medical, endoscopic and surgical management of patients with achalasia. Keywords including achalasia, Heller’s myotomy and balloon dilatation were used and relevant articles included.

MANAGEMENT

Diagnosis

All patients presenting with dysphagia should initially be investigated with OGD to exclude a mitotic lesion. OGD has little value however in diagnosing achalasia but remains an essential component of the investigation of the upper gastrointestinal tract. The gold standard for diagnosing achalasia is oesophageal manometry^6,7. This typically shows a high resting pressure in the lower oesophageal sphincter which fails to relax on swallowing with associated impaired oesophageal contractility. A barium swallow may show very little in early disease, but in more advanced disease may demonstrate a ‘bird’s beak’ appearance or a sigmoid oesophagus, distension due to longstanding obstruction at the gastro-oesophageal junction (GOJ)⁸.

Achalasia Subtypes

Whilst the diagnosis of achalasia is dependent upon the above, high resolution manometry can further classify achalasia into three subtypes dependent on the pattern of oesophageal peristaltic abnormalities and oesophageal pressure dynamics (Figure 1). The three subtypes differ in responsiveness to treatment and as such, can be used to guide the most appropriate treatment and counsel patients appropriately.

Figure 1: The Chicago classification for achalasia subtypes⁹

Treatment

The treatment for achalasia is aimed entirely at symptom control. The underlying pathological processes which lead to myenteric plexus neurodegeneration are not fully understood and as such, cannot as yet be prevented or reversed. Current treatment options exist therefore to reduce the contractility of the lower oesophageal sphincter and hence improve the obstruction to passage of food and symptoms of dysphagia.

Various options exist for this, including pharmacological therapies which are available in the form of nitrates, calcium channel blockers, anticholinergic agents and beta agonists. Endoscopic therapy is a preferable alternative, with pneumatic balloon dilatation or intrasphincteric Botulinum toxin injection being the most commonly used techniques. The ultimate and generally accepted optimal treatment, however, is the surgical Heller’s myotomy (Figure 2).

Figure 2: Treatment options available for the management of achalasia

Medical

Pharmacological therapies as treatment for achalasia have been largely superseded by improvements in both endoscopic and surgical techniques. However, their potential role still exists in those with early disease, in elderly patients unsuitable for surgery or dilatation and in whom Botulinum toxin injections have failed. They may also have potential use in patients awaiting surgery for interim symptom control^10,11,12. Most trials reviewing the effect of drug therapy for achalasia are limited by small numbers and short follow up so long-term benefits remain poorly understood¹³.

As with all achalasia treatments, the aim of drug therapy is to relax the lower oesophageal sphincter. Nitrates have been used as vasodilators within cardiovascular disease since the 1970s. Within the smooth muscle of the gastrointestinal tract, they behave similarly by increasing the production of cyclic GMP and in turn, causing dephosphorylation of the myosin light chain and subsequent inhibition of smooth muscle contraction. It is with this concept in mind that medical treatment with nitrates can cause relaxation of the lower oesophageal sphincter. There are only two randomised controlled trials which have reviewed the effect of nitrates on patients with achalasia and compared them to alternative treatment modalities^14,15. However, as a Cochrane review has established, the results of these studies cannot be reliably interpreted due to both the methodology and the limitations with regards to follow up¹³. Regardless, nitrates are not without side effects and can cause headaches and changes in blood pressure. In view of this, their routine use is not recommended.

Calcium channel blockers, including Nifedipine, are more commonly used and are given sublingual 15-30 minutes before meals¹⁶. These limit the intracellular uptake of calcium and hence reduce the contractility of muscle cells. Reports of success as high as 65-80% have been documented^17,18,19. However, up to 30% experience significant side effects.

Additional agents that have been described include β₂- agonists, anticholinergics and phosphodiesterase inhibitors, the latter of which induces nitric oxide release and thereby relaxation of lower oesophageal sphincter muscle but can also result in significant side effects, including angina, and so routine use is again not advised^20,21. It is for these reasons, that progress has been encouraged elsewhere with developments in both endoscopic and surgical techniques for the treatment of achalasia.

Endoscopic

Endoscopic treatments are again aimed at reducing the contractility of the lower oesophageal sphincter and several options exist for this. Injection of Botulinum toxin A is the most commonly performed and has fewer associated side effects and complications than its alternatives, hence is often used as first line treatment and especially in patients not suitable for surgical intervention. Alternative options include pneumatic balloon dilatation and more recently, per-oral endoscopic myotomy (POEM).

Botulinum toxin A is used as an intrasphincteric injection and exerts its action by inhibiting the release of acetylcholine, necessary for muscular contractions. This in turn lowers the tone and pressure of the lower oesophageal sphincter. 80-100 units of Botulinum toxin A are injected in divided doses in all four quadrants at the level of the squamocolumnar junction via endoscopic guidance. Patients recover quickly and can go home the same day²², typically seeing improvements in symptoms between days 1-3²³. Results are variable. Certainly the side effects are minimal and it appears to be a safe procedure without the risk of perforation seen with other techniques^24,25. Short term improvement in symptoms is described as high as 85%. However, over time this is seen to decrease significantly to only 30% at one year. Most will require further injections or alternative treatments such as pneumatic balloon dilatation or surgical myotomy²⁴.

Pneumatic balloon dilatation includes inflating a 30mm balloon at the level of the GOJ^26,27. This process fractures the muscular fibers of the lower oesophageal sphincter hence disrupting the sphincter mechanism. It can be performed under fluoroscopic or endoscopic guidance dependent on operator experience and preference. The major risk is oesophageal perforation, which in experienced hands occurs in 1.9% (range 1-16)²⁸. In addition, gastro-oesophageal reflux post procedure can be troublesome, affecting 4-16% of patients²⁹.

A Cochrane review compared outcomes with Botulinum toxin injections and pneumatic balloon dilatation³⁰. Whilst little difference in short term improvement was noted, longer term remission rates were considerably higher in those treated with balloon dilatation. However, even with balloon dilatation, up to a quarter require further treatments at five years^31,32.

An emerging endoscopic technique is the peroral endoscopic myotomy (POEM). This is performed by incising the mucosa endoscopically, dissecting and developing a plane in the submucosal layer and performing a myotomy inferiorly to beneath the gastro-oesophageal junction. The mucosa is thereafter closed with staples. Studies have shown it to be both safe and effective with short term results demonstrating similar relief in dysphagia and improvements in Eckardt scores as patients undergoing laparoscopic myotomy^33,34. The added benefit of POEM is the potential for faster return to normal activities³⁴ and with preserving the need for surgery, dissection at the hiatus can be avoided which may reduce symptoms of post-operative reflux. However, it is technically challenging and studies demonstrating long term outcomes are not yet available.

Surgical

The surgical treatment for achalasia involves performing a myotomy at the level of the gastro-oesophageal junction. There has been controversy regarding the most appropriate method of achieving this and experience includes open versus laparoscopic, transthoracic versus transabdominal. Further controversy exists in the importance of performing simultaneous antireflux surgery.

With the development of laparoscopic abdominal surgery, there is little doubt that this has lowered the complications and improved patient recovery and inpatient hospital stay^35,36,37. Not only is the approach to the GOJ easier via the abdomen, also single lung ventilation is not required and so pulmonary complications are fewer.

Surgical myotomy offers superior long-term relief of achalasia-related symptoms compared to medical and endoscopic alternatives, alleviating dysphagia in 88%-94% at ten years following surgery^36,38. Improvements have also been demonstrated in patient satisfaction and quality of life post operatively³⁹. Performing a complete myotomy is essential to outcome and prevention of recurrent symptoms, hence accuracy and precision is paramount⁴⁰. Where this is concerned, robotic surgery is becoming more accessible and early results would suggest improvements over conventional laparosopic surgery⁴¹.

The risk of perforation is small with laparoscopic myotomy⁴² and even smaller with robotic surgery. The main complication associated with performing a myotomy is symptomatic reflux. Controversy exists regarding simultaneous anti-reflux procedure and some would argue that in the absence of posterior dissection at the level of the GOJ, there is not the need⁴³. A meta-analysis performed by Lyass et al reviewed patients undergoing surgery for achalasia⁴⁴. The authors concluded that the rates of reflux post operatively were no different between those who had anti-reflux procedures and those who did not. Ultimately, the decision to proceed with anti-reflux surgery will vary surgeon to surgeon. However, what is generally accepted is that a complete 360 degree Nissen’s fundoplication is not required, and may serve only to give the patient ongoing symptoms of dysphagia. Therefore, Toupet (posterior 270 degrees) or Dor (anterior 180 degrees) fundoplication are more commonly used, the latter providing cover to the myotomy and thus potentially protecting any unidentified mucosal breach⁴⁵.

Surveillance

Studies have demonstrated that patients with a diagnosis of achalasia have an increased risk of squamous cell carcinoma of the oesophagus⁴⁶. For this reason, guidelines developed by the American Society for Gastrointestinal Endoscopy suggest surveillance oesophagogastroduodenoscopy every 1-3 years for 15-20 years⁴⁷.

CONCLUSIONS

Achalasia is a difficult condition to diagnose and treat. All treatments are aimed at disrupting the lower oesophageal sphincter mechanism and none are without risk or complication. Treatment modalities vary in their short and long term success rates. Pharmacological treatments are of limited value and Botulinum toxin injections have limited long term results but both may play a role in patients who cannot tolerate more invasive procedures⁴⁸. The main debate has historically lain between advocating the use of endoscopic dilatation versus laparoscopic Heller myotomy.

Studies looking at endoscopic dilatation versus myotomy have comparable initial symptomatic relief. Direct comparison between the long term outcomes does, however, favour laparoscopic myotomy^49,50. Traditionally, endoscopic dilatation has been the first line treatment, with surgery reserved for those in whom dilatation has failed⁵¹. However, subsequent intervention is common and there are many studies examining outcomes of second treatment with either surgery or dilatation. In cases where initial treatment has failed and recurrent symptoms of dysphagia present, dilatation has been shown to be more effective in those who have had surgery rather than those who have had previous dilatations or Botulinum toxin injections^52,53. Importantly, there is not a greater risk of perforation in these patients than in those who have not undergone myotomy⁵⁴.

Performing a surgical myotomy after previous treatment with dilatation or injection may complicate the surgery slightly and has been shown to increase complications and failure of myotomy^55,56, providing an argument for surgery as first line treatment. That said, surgery is still recommended in these patients as the most successful option⁵⁷.

Ultimately, the optimal treatment will vary dependent on physician or surgeon technique and experience. Cases are limited and so it is recommended that these patients are treated in a specialist Upper GI unit where all options are presented to the patient and the risks and benefits of each counselled appropriately. It is an exciting time for achalasia as new treatment options including POEM come to light and robotic surgery becomes more available.

Effectiveness of homeopathic remedies continues to be a question of concern for public, policy makers and the other involved stakeholders. A recent systematic review of studies by Australian National Health and Medical Research Council (NHMRC) ¹ heightened further the concerns about the perception of effectiveness of homeopathic treatments in general. After an exhaustive review, the authors found no good quality, or well-designed studies with adequate sample size to support claims made by homeopathic practitioners. They concluded that the homeopathic remedies are no better than a placebo. Authors of the report cited concerns about the designs of the most of the studies especially the ones that showed any beneficial effect. Authors noted that such studies either had smaller sample sizes, were conducted poorly and/or were insufficiently powered to detect a statistically significant outcome. NHMRC concluded that there is no evidence from systematic reviews regarding the effectiveness of homeopathy as a treatment for any clinical condition in humans. The NHMRC identified “claiming benefits for human health not based on evidence”¹ as a major health issue in Australia.

NHRMC’s report comes as no surprise as many other exhaustive reviews had failed to show any objective benefits of such remedies. Authors of a 2009-10 UK report titled as Evidence Check 2: Homeopathy², reached to a similar conclusion. They questioned the lack of homeopathic treatment trials and cited that there is plenty of evidence showing that it is not efficacious. Their conclusion was no different from NHRMC’s and proposed that “systematic reviews and meta-analyses conclusively demonstrate that homeopathic products perform no better than placebo”². They further recommended stopping any public funding of Homeopathic remedies in UK. Although a Swiss report³ argued otherwise claiming that homeopathy is a “valuable addition to the conventional medical landscape”³; however its methodology was considered to be flawed, biased, misinterpreting and discrediting the current science based study methodologies⁴.

The homeopathic notion of successive dilution of its products in water increasing the potency of the final product and “like cures like” doesn’t only defy any science based medicine logic, it is also in contrast to other alternative systems of medicine. The paucity of good-quality studies of sufficient size that examine the effectiveness of homeopathy as a treatment for any clinical condition in humans does no favors to this notion either. As cited by many reports referenced above, the available evidence is not compelling and fails to demonstrate that homeopathy is an effective treatment for any of the reported clinical conditions in humans. In spite of these significant concerns about the legitimacy and efficacy of homeopathy, the industry continues to benefit from public’s increasingly favorable attitudes toward homeopathy. The National Institutes of Health⁵ in the United States, reports that there is little evidence to support homeopathy as an effective treatment for any specific condition however millions of American adults and thousands of children use homeopathy. Even in UK⁶ where there is no legal regulation of homeopathic practitioners, The National Institute of Health and Care Excellence (NICE)-that advises the NHS on proper use of treatments, doesn’t recommend that homeopathy should be used in the treatment of any health condition. However homeopathy has seen a significant increase in its market share not only in UK but many other European countries too⁷.

With its market share in USA and rest of the world markets reaching in billions of dollars with yearly incremental increase, its claims for its remedial effects albeit lacking any generally acceptable evidence, raises concern that a vulnerable person may choose an ineffective remedy that may actually worsen their clinical status. There is a clash between patient autonomy and informed consent in decision making by a vulnerable patient about the appropriateness of homeopathic remedies. The ethical and policy debate on the appropriate balance between public’s access to different remedies (autonomy) and government institutional duty of public’s protection from potentially harmful or ineffective medicines is a delicate balance.  An objective and thorough evaluation of homeopathic remedies is needed however how to decide what is an objective and accurate way to assess homeopathic research continues to be the bone of contention. Although from a science based medicine perspective, homeopathic remedies have no scientific explanation, its advocates^{3, 4} don’t agree that it has to fall or go through same process of research methodology for its effectiveness as do allopathic remedies. Though it is a valid logic that reasoning directly from data that is gathered by controlled structure, as is true of science based trials in allopathy, is not always accurate as it’s with many biases and confounders, however the statistical testing helps to get beyond mere correlation to cause-and-effect and eliminate most of these concerns. These trials also help to formulate conclusions that can be further validated or refuted by gathering real world data. The mainstream science considers the homeopathic notion of ultra-dilutions, particle leaving imprint of itself on water, and “likes cures like” to be scientifically implausible. Even though this notion of scientists may be considered as a bias towards evaluating any homeopathic remedy, the public health institutions have an ethical obligation to educate public especially the vulnerable ones, not to substitute a proven and effective treatment for the ones whose effectiveness has not been scientifically proven.

As the saying goes, “change the rule and you will get a new number”, the onus is on homeopathic advocates not only to design trials, gather data, and publish papers but also to collect real world data to further study the impact of treatments on outcomes. The real world data can further help to understand the effects of treatments on patient outcomes that was not generated from a clinical trial. It is also an obligation of the homeopathic practitioners and organizations to seek to create standards of medical treatment, that are objective, replicable, and that will be made broadly available to physicians, researchers, parents, policy makers, and others who want to improve the care of individuals. As recommended by many exhaustive reviews^1,2, these studies should recruit larger samples of patients, utilize methodologies that eliminate the bias, better discoverable record keeping for proper reporting and follow up, an objective analysis of outcomes data and how they were measured, and better discussion of potential confounders or biases. Besides they have to adequately and accurately report study details including treatment regimens, length of follow up, outcomes studied and the clinical and statistical significance of results. 

Going by the logic of famous words attributed to the noted statistician and management scientist, W Edwards Deming, “In God we trust; all others must bring data,” the ball is in their court.

BACKGROUND

Suicide and deliberate self-harm (DSH) have been recognised as major public health problems in India for some time, but there are significant obstructions to effective intervention including difficulties in following Western models to understand these behaviours.^{1, 2, 3}

The World Health Organisation (WHO) recognises suicide as one of the three leading causes of death in young adults globally.⁴ The greatest burden of suicide is now in low- and middle-income countries like India where annual suicide rates are 10-11 per 100,000.^{5, 6, 7} India is second only to China in the absolute number of annual deaths by suicide.⁵ The number of individuals who die by suicide each year in India alone is more than the total number of suicides in the four top ranked European countries combined.^{3, 5, 8}

DSH, defined as intentional self-poisoning or self-injury, is a closely related public health problem.⁹WHO estimates that for every suicide there are at least 10-20 DSH acts.¹⁰ If this estimated proportion, based on Western research, is also true in India then there are 1-2 million DSH acts in India each year.

Official data for 2005 suggest that 19.6% (n=22,327) of India's 113,914 officially recorded suicides were self-poisonings with pesticides⁷ (predominately organophosphates, which are freely available and widely used in agriculture). The official suicide rate for India, 10.3 per 100,000 in 2005,⁷ is thought to be an under-estimate.^{3, 11} Studies from several regions suggest that India's suicide rates may be as high as 40 per 100,000 and that 30% or more of these deaths are due to pesticide self-poisoning.¹¹ The studies reporting the highest suicide rates within India are from Tamil Nadu (>60 per 100,000 – three times higher than the official figure for the state).^{12, 13, 14, 15} Whilst some of the discrepancies between official statistics and findings in local studies may be due to urban-rural differences in the incidence of suicide, data collated by the Indian police suggest that around 90% of suicides in India occur in non-urban areas.^{7, 11, 15} Extrapolating from these figures, it is conservatively estimated that there may be up to 420,000 suicides per annum in India (126,000 from pesticide self-poisoning).

India's centrally collated self-harm and suicide data are unreliable owing to a number of factors. Death registration processes are below Western standards. Only about 25% of deaths are registered and only about 10% are medically certified.^{16, 17} Attempted suicide is a crime in India.¹⁸ Survivors are interviewed by the police. Fear of legal and social consequences following an act of self-harm probably influence willingness to acknowledge DSH and preparedness to seek medical intervention.

India contributes almost 20% to the world's population, and suicides rates are increasing particularly amongst the young.^{11, 19} Obtaining reliable and nationally representative data on DSH rates in India should be a priority for health-funding agencies over the next decade. In order to reduce fatalities following self-harm, information and investment are needed to improve quality, affordability and accessibility of health care close to the affected communities.²⁰

If, as seems likely, self-harm (especially pesticide poisoning) occurs predominantly in rural areas of India,¹¹ Western models of data collection and intervention aimed at reducing pesticide poisoning (which is predominately accidental in developed economies) are likely to require significant modification to be reliable and effective. The WHO's global suicide prevention strategy is largely based on findings from research and models of suicide prevention developed in the West.²¹ Health care resources in rural areas of India are thinly spread, and are often rudimentary compared to those in the West. There is an urgent need for research in low- and middle-income communities – particularly in rural areas of India – to provide the evidence base to underpin public health strategies for preventing pesticide suicides in these countries.

The establishment of DSH registers is a first step towards the systematic collection of data in relation to self-harm, both for epidemiological purposes and to understand pesticide self-poisoning at an individual level. If DSH registers can be shown to generate reliable information in India, in due course it may be possible to identify the factors that put individuals at risk of behaving in this way, and create relevant evidence-based policies to develop interventions for reducing mortality and morbidity associated with DSH (particularly pesticide poisoning).

This paper explores the feasibility of setting up a DSH register in a resource-poor large State hospital in south India, where rates of suicide and DSH are high.

METHODS

Setting

This study was carried out at Mysore Medical College and Research Institution (MMCRI), a State-run hospital in Mysore, southern India. The hospital serves a catchment area of 1,500,000 population and 135 primary health centres. The hospital has most specialities, with 1050 beds and a 10-bedded intensive care unit. 800-1000 patients attend the hospital outpatient department daily. Daily attendance to the casualty department for the purpose of medico-legal registration (which includes self-harm) is between 110 and 130. All other presentations including emergencies are managed through respective speciality outpatient departments.

Figure 1. Care Pathway for deliberate self-harm (DSH) at Mysore Medical College and Research Institution (MMCRI)

Setting up of the register

The flow diagram (Fig. 1) illustrates the care pathway of those presenting with DSH to MMCRI highlighting that only a few receive psychosocial assessment. A working group of psychiatrists, psychologists, social workers, casualty medical officers, statisticians and hospital managers was formed to arrive at a consensus on the minimum dataset that could be gathered from DSH survivors for the purpose of setting up a register. Literature on establishing self-harm registers was reviewed along with international guidelines in relation to self-harm assessment in the general hospital.^{22, 23} Opinion was sought from senior psychiatrists and public health personnel from the private and public sector in Mysore and from the United Kingdom (UK). The team was visited, supported and advised by the Centre for Mental Health and Society, Bangor, UK.

The items listed in Table 1 were considered as ‘minimal yet essential’ for informing clinical practice, service development and patient engagement in future research. The study was not externally funded and, due to time and resource implications, it was agreed that outcomes of mental health assessments would not be recorded in the register. The method of DSH was coded according to the International Classification of Diseases 10^th Revision (ICD-10) criteria²⁴ and socio-economic indicators were derived from a modified Kuppuswamy’s scale²⁵ that is validated for the south Indian urban population.

Table 1. Contents of the deliberate self-harm (DSH) register.

An electronic DSH register was set up in February 2013 and is currently held in the Department of Psychiatry, MMCRI, and Mysore. Two pre-registration House Officers (junior resident equivalent) visited the casualty department daily and identified those cases registered as self-harm from both the standard patient register and medico-legal case registers. If the individual was discharged from casualty (condition necessitated no further treatment, no intensive care bed available, or patient chose admission in private sector after first aid) the available information is captured from the registers and medical records. If they admitted to the general hospital they were traced and personally contacted. Information (as in Table 1) was collected from DSH survivors and from medical records. The data was verified by a Consultant Psychiatrist before being entered in the register. DSH survivors are asked to provide two contact details (postal address and phone number) for future tracing if they consent to further contact either in person or by phone. Table 2 is a list of the sources of data for the DSH register in Mysore and their limitations.

Table 2. Sources of data for deliberate self harm (DSH) register in Mysore and their limitations.

Feasibility

A DSH register should be representative, complete and accurate. The register should be acceptable to the entrants and only take a minimal time for data collection and registration. For the purpose of this study the following were identified as indicators of feasibility:

· Time between identifying that the patient should be included in the register and completion of data entry in the register. This was recorded for 80 randomly chosen inpatient DSH survivors.

· The proportion of patients presenting with alleged DSH who were correctly identified and, if admitted to the general hospital, traced for the purpose of inclusion to the register (representativeness).

· Proportion of those included in the register for whom a full data set could be captured (completeness).

· Proportion of the DSH survivors who were willing to be included in the register and provided contact details for future follow-up (acceptability).

· Over a period of a week, every month during study period February 2013 to July 2013, a Consultant Psychiatrist independently collected data from casualty registers and checked against the total number registered on the DSH register for the corresponding month (accuracy).

RESULTS

Between February 2013 and July 2013, a total of 19,563 patients attended the casualty department. Of these, 1072 attended in relation to self-harm. 1041 of them were hospitalised for further intervention. All of those who were hospitalised and survived (n=817) were traced and contacted. None objected to their details being entered on the register. However, only 253 of the 817 (30.9%) agreed to be contacted for future follow-up. Of the 817, only 109 (13%) had been formally referred to the psychiatry department for an assessment prior to contact with the research team. None of the 817 had any involvement with Social Services.

Out of the 1023 on the register, complete data was available and/or obtained for 740 (72.3%) individuals and data was incomplete for 283 (27.7%) patients. Either by reviewing the medical records or interviewing the patient, it was confirmed in all 1023 cases that there had been an act of self-harm necessitating medical intervention. The time between identifying that the patient should be included in the register and completion of data entry in the register varied between 30 minutes and 2 hours. When the data collected was cross-verified (n=315) by a Consultant Psychiatrist (author RR), entries of 310 individuals were accurate, with a minor discrepancy in less than 3 items for another 5 individuals.

Various terminologies were used to report a case of DSH in the case records (for example, suicide attempt, failed suicide, self-harm, poisoning, deliberate harm).

DISCUSSION

This is the first description of a method of successfully setting up and maintaining a DSH register in an Indian setting. It was a labour-intensive exercise due of lack of electronic patient data management, administrative support and the absence of an agreed care pathway for DSH in the hospital. Despite these obstructions, we have illustrated that it is feasible to set up a DSH register in a busy tertiary care hospital in India. Results of our study indicate that the register details are accurate and representative of those who seek help from the specialist centre. However, it cannot capture those patients whose DSH was managed successfully within primary health centres, those individuals who failed to seek help and those who died before admission.

Clinical Implications

The experience of establishing a DSH register has lead to changes in local clinical practice. DSH is associated with increased morbidity and increased utilisation of health services.²⁶ DSH survivors who were contacted (n=817) by the psychiatry residents were offered psychosocial assessments. Under normal circumstances, 708 (87%) of this group would not have received any psychosocial assessment. The process of setting up the register has helped to identify DSH cases so that an intervention can be offered before discharge from the general hospital. The register has also played a major role in the identification of people who harmed themselves but were discharged without admission to a ward. This group can also be helped. We have now developed an education and service information leaflet which includes emergency contact details (similar to a crisis card in the UK), which is given to DSH patients on discharge. These are known to decrease the repetition of DSH in the developed world.²⁷ Deaths from suicide are largely preventable if knowledge and understanding of this maladaptive behaviour is used to ensure timely intervention.⁸

By auditing DSH data in a systematic way, clinical decision-making will be based on pooled experience, not just on each clinician’s recall. Comprehensive registers of DSH provide clinicians with the opportunity to review cases of suicide where they have had clinical involvement, using techniques such as psychological autopsy, improving clinical skills and judgements. Overall there is a need for an attitude of vigilance about suicide risk, and of enthusiasm about pursuing initiatives for suicide prevention based on evidence. Better understanding of self-harm will assist in devising means of reaching out to those at risk of dying without having had contact with health care services.

Reporting of DSH in case records was inconsistent. There is a need for uniform recording, medical coding and reporting of DSH. In the DSH register, the method of self-harm is recorded using an international recognised coding system (e.g. ICD-10).

If we continue to offer psychiatric assessment to all cases of DSH, the much higher rate of ascertainment arising from the DSH register will place further strain on an already stretched psychiatric service. Further investment in services specifically targeting self-harm in India is urgently needed.

Service Implications

Use of the register

The register creates an opportunity for a standing DSH audit, allowing for identification of trends over time and comparisons with other services that establish DSH registers using similar methods. Systematic collection of demographic and clinical data will allow calculation of admission rates, repetition rates and other indices of importance in service development. Collaboration with non-governmental organisations in the region who work with those who self-harm will allow development and evaluation of specific culturally appropriate interventions.

Where the register should be held?

In the developed world DSH registers are normally held on electronic systems in the Accident and Emergency department or liaison psychiatric services. In India, it is a mandatory obligation to hold a medico-legal register (which includes DSH) in casualty. Maintaining an additional DSH register risks unnecessary duplication, but modification of a medico-legal register creates an ethical problem and risks under-reporting. There are few liaison psychiatry services in India. On balance, we suggest that our practice of holding the DSH register within the department of adult psychiatry is the optimal arrangement in the Indian setting.

Confidentiality

Confidentiality must be respected. In the UK, when establishing a DSH register, it is necessary to discuss issues of confidentiality and legality with the local Data Protection Officer, and to register under the Data Protection Act. Use of the data for research purposes requires approval from local Research Ethics Committees. In India, there is little regulation of this sort. In order to establish our register it was only necessary to obtain consultant approval and consent through the local medical committee. We suggest that good practice would demand that standards of confidentiality and oversight should, as far as possible, match Western standards.

Manpower and resources

Setting up this register in Mysore required input by a Consultant Psychiatrist, for 2 sessions per week for 6 months, to negotiate with casualty medical officers, consultant physicians and reception staff. The resident from the psychiatry department spent at least 2 hours a day collating and updating the register. The absence of a patient electronic data system and lack of administrative support has placed additional strain on residents and has prolonged the time to identify a case of DSH from the casualty records and trace them on the medical wards. We believe that once the register is established, these tasks could be managed by a trained Social Worker spending 1 session per day collecting the data and 1 session per week editing the register. The work load might vary in other hospitals, depending on the number of daily hospital attendances for DSH.

Integration with other data sources

Linking this register with post mortem records, local civil registration of deaths and police records is desirable but this needs co-ordinated effort from several civil bodies and public health organisations. In the absence of any legislation or national record linkage systems, there are few motivators to drive this change or the allocation of resources. However, a unique person identification number system is presently being rolled out across India. The development of cross-agency electronic databases will facilitate easier record linkage in the future, which creates the opportunity for collection of reliable and representative data at a regional level.

None of those who were contacted during the study period had any formal input from Social Services. Though the models and mode of delivery by Social Services in India is radically different to those in Europe, DSH survivors form a stigmatised vulnerable group who are frequently in need of social assessment and support.

Future investment and development

There are good humanitarian reasons to seek the de-criminalisation of acts of self-harm in India, and there is presently strong lobbying to bring this about. It is reasonable to suppose that this might lead to readier help-seeking and better reporting of self-harm and suspected suicide. However, there are other measures that would be necessary to reduce rates of DSH and completed suicide. Regulating the supply of organophosphate insecticides, so that they are only available in dilutions that make fatal overdose more difficult, would be one such measure. There is also a need to develop liaison psychiatric services, offering psychosocial assessments to a higher proportion of those who present with features indicative of probable self-harm. Other necessary developments include investment in patient electronic records and systematic strategies for destigmatisation of DSH.

The register has provided us with a cohort of individuals who are willing to be contacted for future studies. The register has continued beyond the study period. We presently have 3720 individuals on the register. The unit has established formal links with research centres in the UK. We intend to carry out longitudinal studies to examine the patterns of DSH, rates of repetition, compliance with follow-up and suicide rates. This will help to identify the culture-specific access, adherence and prognostic factors, and will influence the development and validation of brief psychosocial interventions in a social, economic and cultural context that is radically different to the West.

CONCLUSIONS

We have illustrated that it is feasible to set up a DSH register in a busy tertiary care hospital in India where rates of self-harm are high. Results of our study indicate that the register details are accurate and representative of those who seek help from the specialist centre.

Very few were referred for psychosocial assessment following an act of self-harm and none of them had any formal input from Social Services. Though the models and mode of delivery by Social Services in India is radically different to those in Europe, DSH survivors form a stigmatised vulnerable group who are frequently in need of social assessment and support.

Case report

A forty-eight year old man presented with unusual and distressing visual experiences with varying degrees of severity for over twenty years. Some of these included the following; red objects having a green shimmer around them like 3-D glasses, altered sense for distance estimation, people’s faces seeming to change shape when looked at, alteration of own reflection, anything patterned appearing to move all the time, words moving about while reading, things appearing to be multi-layered, bright lights throwing up shadows, vehicles appearing to stretch as they drive past, flying birds looking like animation and difficulty in focussing.

When present, his symptoms interfered markedly with his functioning. For example, he could not cross the road, could not read, and had to dim his lights. He struggled with knowing which visual perceptions were real and which were not. The patient felt his visual experiences were related to his past LSD use twenty-five years ago. He felt the drug had put him “in a coma” and he was “dreaming all of this”.

He specifically remembered a party with friends where he took a cocktail of illicit drugs, including LSD and marijuana, with alcohol. He said he would usually take drugs and alcohol in a binge pattern. The ‘trips’ would usually last twelve hours. He felt he experienced some memory loss of that particular night. When he woke up the next morning he was still experiencing the effects of LSD and said he has felt these effects ever since. He tried to explain that it was like drinking alcohol, waking up drunk and being drunk from that point on. After this incident he did not use illicit drugs again.

Prior to this particular night he said he may have used LSD about fifteen times, as Microdot tablets, usually one at a time, with cannabis. He said it was “like having a tripping switch in your brain”. When you took LSD, “the switch turned the tripping on and after a while it turned off”. He said his switch “was broken” and he therefore continued to re-experience the effects of the drug.

His other complaint was that of feeling he was “not real”; to the extent he even thought he should harm his family members so he could prove he was real.

He also complained of low mood, decreased concentration, anxiety and an inability to cope.

His first contact with mental health services was at the age twenty two years. He presented with symptoms of anxiety but it was not felt he had a mental illness. He was referred again a year later and was diagnosed to have Primary Depersonalization syndrome.

The patient himself reported that all his symptoms started after he had used LSD about fifteen times in six months. At the time he had described having undergone a complete personality change due to his experiences. He felt objects and experiences had a dream-like quality. His visual experiences caused so much distress he felt suicidal.

Over the next twenty-five years he has had various other diagnoses; LSD induced Depersonalisation Syndrome, Depersonalisation-Derealisation Syndrome, LSD induced Simple schizophrenia, depressive disorder and anxiety disorders. His visual disturbances had been interpreted as visual hallucinations. He had received treatment with antidepressants (Imipramine, Amitriptyline, and Venlafaxine); antipsychotics (Trifluperazine, Promazine); Benzodiazepines (Diazepam); Propranolol; and Fentazine. He was also prescribed Hydergine (which helped reduce symptoms briefly) at one point.

Investigations: EEG, MRI Brain, and Carotid ultrasound were normal.

He was admitted to a psychiatric hospital at the age of forty-eight years old where the admitting doctor described his symptoms as visual hallucinations and started him on Risperidone, which increased the intensity of his symptoms. He was also treated with Citalopram for his low mood. It was noted that his symptoms were different from common psychotic illnesses. Detailed history taking and assessment of his perceptual abnormalities over the following few weeks in hospital confirmed the diagnosis of hallucinogen persisting perception disorder (HPPD).

He was treated with Clonazepam 1 mg four times a day with good effect; as seen by the reduction of symptoms - see Table 1.

Table 1:

After discharge he had .a depressive episode and was treated with Escitalopram. This was later changed to Reboxetine.

Discussion:

This is the first case that we are aware of where symptoms of HPPD have persisted for over two decades after the cessation of the use of Lysergic acid diethylamide. There is a need for raising awareness about this condition to prevent misdiagnosis and delay in appropriate treatment.

This patient presented to psychiatric services over twenty-five years ago and at that time he felt his symptoms were related to his use of LSD. He was given a variety of different diagnoses before the correct diagnosis was established and treatment initiated with good outcome.

The patient had also experienced migraines and used alcohol excessively on occasions in the past. Although we are not aware of any connection between this disorder and these factors, future reports and studies may help provide further knowledge in these areas.

HPPD is a recognised condition described in DSM V and DSM IV with a diagnostic code 292.89. In DSM III it was referred to as post hallucinogen perception disorder (PHPD). It is described in ICD 10 under the code F16.983.

LSD has been known to alter perception and mood in the presence of an unaltered sensorium. HPPD was first described by Eisner and Cohen, who observed spontaneous recurrences of LSD like states in subjects, days to weeks following cessation of drug use¹.

Other authors have described more or less the same clinical picture; for example, Rosenthal described patients suffering from post drug visual hallucinations lasting as long as five months from the time of drug use²

In a survey of sixty five users of LSD, Holsten found fifty users who described post LSD disturbances eighteen months to four years later³.

Flashbacks have been suggested to be a misnomer as patients described cases of continuous rather than paroxysmal visual disturbances from LSD ⁴

It is not clear what made our patient re-experience these visual disturbances however the literature suggests that emerging into a dark environment can precipitate or exacerbate post LSD visual symptoms. Among other precipitating factors are intentional inductions, marijuana use, medications like: neuroleptics (phenothiazine), amphetamines, cold remedies, anti-Parkinson’s agents and SSRI’s⁵.

The patient mentioned that he had ingested LSD approximately fifteen times before he developed this condition. The data suggests that peak incidence occurs with fifteen exposures and second smaller peaks at around forty to fifty exposures ⁶.

A number of hypotheses have been formulated in order to understand the underlying aetiology. HPPD is related to the recreation of symptoms experienced in intoxication. LSD has been shown to be excitotoxic to neurons. It is also known to be a partial agonist at post synaptic 5HT2 receptors and enhances glutaminergic transmission.

The patient had suffered from these rather distressing visual disturbances for more than two decades, which have had considerable impact on his daily living. He was given different diagnoses which included Induced depersonalisation, depersonalisation-derealisation syndrome, LSD induced simple schizophrenia, depressive disorder and anxiety disorders.

The patient had been treated with different psychotropic medications including antidepressants, antipsychotics, benzodiazepines, propranolol, fentazine and hydergine. Some had little effect like hydergine, whilst others worsened symptoms, in particular antipsychotic medications.

A case series of three HPPD patients treated with Risperidone reported an exacerbation of LSD-like panic and visual symptoms. Thus from these reports and our case report Risperidone could be contraindicated in patients with HPPD ⁷.

There have been some published case reports on treatment of HPPD, including the use of Reboxetine, which suggest it is beneficial in the treatment of the visual disturbances and depressive features associated with HPPD. This is possibly due to its alpha 2 adrenoceptor modulating effect on both Noradrenaline and Serotonin release⁸_. Another case report suggested the use of a combination of Fluoxetine and Olanzapine in the treatment of HPPD⁹.

Benzodiazepines seem to be the most beneficial treatment so far and Clonazepam is the most effective due to its high potency compared to low potency Benzos and its long action at the GABA receptors¹⁰.

Conclusion:

Hallucinogen Persisting Perception Disorder is one of the outcomes associated with the ingestion of LSD. Symptoms can be present for years as demonstrated by different case reports, and for over two decades as reported in this report. The effect could be devastating to the person experiencing extremely distressing and disturbing perceptual phenomenon. It can last up to twenty five years after the cessation of the hallucinogenic drug. Early diagnosis and appropriate treatment can significantly help improve the quality of life of patients with this condition.

Case report

A 36 year old multiparous woman presented to the Labour Ward at 33 weeks’ gestation with lower abdominal pain. She had mild asthma and her obstetric history included 2 previous normal vaginal deliveries.

At 16 weeks’ gestation she was found during antenatal scanning to have a right ovarian cystic lesion measuring 59x34x50mm. This was monitored and a repeat scan at 25 weeks’ showed it had increased in size to 73x55x47mm.

At 32 weeks’ she was diagnosed with a DVT and was commenced on therapeutic enoxaparin (stopped two days before current presentation). (D-Dimer > 4000micrograms/L). An inferior vena cava filter was inserted. The patient declined any surgical intervention of the cystic lesion during pregnancy and an early elective Caesarean Section with surgical management of the cyst at 34 weeks’ gestation was planned. She had no symptoms or signs suggestive of a PE and was not formally investigated for one prior her current presentation.

On this presentation at 33 weeks’ gestation, her pain suddenly worsened with associated hypotension and evidence of foetal distress and so an emergency exploratory laparotomy was performed.

Admission haematology results: haemoglobin 10g/dL, platelets 158 x 10⁹ /L, INR 1.0, APTT 28.4 seconds, APTT ratio 1, fibrinogen 3g/L.

She underwent a rapid sequence induction in the supine wedged position using thiopentone and suxamethonium. She was a Grade 1 intubation and anaesthesia was maintained with oxygen/nitrous oxide/sevoflurane and muscle relaxation was achieved with atracurium. A ruptured, torted right ovarian mass containing an estimated one litre of altered blood was noted. At Caesarean section a live male infant was delivered. A right oophrectomy was then performed. The infant was subsequently intubated and transferred to the Neonatal Intensive Care Unit.

Oxytocin 5IU followed by a 40IU infusion over 4 hours was administered following delivery of the baby. Effective haemostats was achieved, the uterus appeared well-contracted and the patient’s abdomen was closed. Surgical blood loss was estimated as 600mls (excluding blood within the ovarian mass).

Thirty minutes following completion of surgery the patient, fresh blood was noted vaginally. A HemoCue* reading was taken as 5.9g/dL. Four units of blood and two units of FFP were transfused whilst a second laparotomy was performed. Fresh blood was noted intra-abdominally and the uterus was markedly atonic. Ergometrine 500mcg and carboprost trimethamine 250mcg were administered intramuscularly, as well as, misoprostol 800mg vaginally. A hysterectomy was performed due to the rate of bleeding and the evident haemodynamic instability.

Coagulation studies: platelets 27 x 10⁹/L, INR 1.4, APTT 101.8 seconds, APTT ratio 3.6 and fibrinogen 1g/L.

A further 4 units of blood, 4 units of FFP, 1 pool of platelets and 2 units of cryoprecipitate were transfused. Factor VII was also administered on advice from the Haematologist.

An internal jugular central venous catheter was inserted and a noradrenaline infusion started. Initial attempts to insert an arterial cannula were unsuccessful as peripheral pulses were difficult to palpate. Venous blood gas readings revealed hyperkalaemia (K+ 6.4mmol/L) which was treated with sodium bicarbonate, 10mls 10% calcium chloride and a continuous 50% dextrose and insulin infusion. Her abdomen was packed and percutaneous drains were inserted. Anaesthesia, close monitoring and resuscitation continued.

Ongoing output from drains prompted a third exploration after an hour. There was generalised oozing particularly around the bed of the resected ovary in the pouch of Douglas.

Coagulation profile: platelets 50 x 10⁹/L, INR 1.4, APTT 89.6 seconds, APTT ratio 3.1 seconds, fibrinogen 1.4g/dL.

A further 10 units of blood, 3 pools of platelets, 5 units of FFP and 3 units of cryoprecipitate were transfused. Sequential coagulation profiles and thromboelastography were used to guide transfusion.

During this exploration, ECG revealed a broad complex tachycardia with no palpable pulse confirming cardiac arrest likely secondary to hypovolaemia and/or hyperkalaemia. Return of spontaneous circulation was achieved after 3 cycles of continuous cardiac massage, 4 direct current shocks and adrenaline 1mg.

A femoral artery cut-down was performed and arterial cannula was inserted by a general surgeon. IABP monitoring commenced.

A fourth exploration was carried out around two hours later for ongoing blood loss. Again only generalised oozing was noted particularly from the oophrectomy site. Her abdomen was re-packed.

Coagulation profile: haemoglobin 7.4g/dL, INR 1.2, APTT 48.9 seconds, APTT ratio 1.7, fibrinogen 1.9g/dL, platelets 94 x 10⁹/L.

She was transferred to the ICU eight hours from the start of the primary operation. Estimated total blood loss was 13,200mls. Transfusions continued and her abdomen was closed two days later. She received haemofiltration therapy for acute kidney injury. She recovered to her premorbid level with no neurological deficit before being discharged with her baby a few weeks later. In total, she was transfused 64 units of blood, 35 units of FFP, 10 pools of platelets and 11 units of cryoprecipitate. Histology of the ovarian mass revealed high grade clear cell carcinoma for which she received chemotherapy but unfortunately she died two years later.

Discussion

The association between cancer and thromboembolism has been well established for many decades.¹Ovarian cancer patients have one of the highest incidences of VTE amongst cancer patients, particularly clear cell carcinoma (CCC). One study found the incidence of thromboembolic complications to be significantly higher in CCC when compared with other epithelial types of ovarian cancer (27.3% vs 6.8%).²

The pathological mechanism behind the hypercoaguable state induced in ovarian cancer patients appears to be largely multi-faceted. A variety of procoagulant subtances may be involved. Of particular interest is tissue factor (TF), a potent procoagulant found in endothelial and blood cells, as well as, in tumour cells. TF may play an important role in this hypercoaguable state through activation of the coagulation cascade.³ TF is frequently over-expressed in ovarian cancer tissue and there is research suggesting it influences tumour progression.^3,4

A hyperviscosity syndrome may also be seen in association with ovarian cancer which favours thrombosis and may accelerate tumour progression and metastasis.DVT is a recognised complicating factor of ovarian cancer which may adversely affect the course of the disease possibly as a component of this hyperviscosity syndrome^5,6 Ovarian cancer patients are also vulnerable to developing cerebrovascular complications and carry a higher risk of developing ischaemic strokes which has a significant impact on morbidity and mortality.⁷

The hypercoagulable state seen in cancer patients can have a spectrum of manifestations that ranges from DIC to massive thromboembolism. DIC in these instances is usually chronic and subclinical.⁸

The degree of coagulopathy which was seen in this case could not be attributed solely to dilutional effects incurred through fluid resuscitation. Instead we propose the acute severe coagulopathy was a consequence of procoagulant factors inherent to neoplastic tissue, including TF, which were suddenly released into the circulation following rupture and surgery to the ovarian tumour. The overall result would be widespread activation of the clotting cascade and a consumptive coagulopathy.

This case aims to increase awareness of a refractory coagulopathy which may be seen following rupture and/or surgical resection of a malignant ovarian tumour. The presence of an ovarian cyst especially in conjunction with evidence of vascular thrombosis in pregnancy should raise suspicion for an ovarian malignancy and hence vigilance for this potential complication. Anticipation of such a severe coagulopathy and associated significant blood loss should pre-empt early establishment of invasive monitoring, ample intravenous access and ensuring quick access to blood and blood products. Bedside coagulation tests such as thromboelastography are useful guides to blood product transfusion.⁹ Prompt mobilisation of resources, multi-disciplinary input and effective team work were crucial factors which facilitated the management of this case.

Acute, severe DIC associated with ovarian intratumoural bleed which resolves following resection of the tumour has been reported previously.¹⁰ This is the first case to the best of our knowledge occurring following ovarian cancer torsion and rupture during pregnancy.

Overview

The term ‘designer drug’, coined in the 1980s, generally referred to various synthetic opioids based mostly on the fentanyl molecule (α-methylfentanyl) and MDMA (methylenedioxymethamphetamine) commonly known as ecstasy. Fentanyl is an extremely potent analgesic, some 100 times more potent than morphine. MDMA and fentanyl compounds were the most popular synthetic drugs initially. The terminology is confusing because although the description ‘designer drug’ seems to imply the creation of new drugs, many are not new. For example, cathinone derivatives have been reported since the late 1920s. MDMA was first synthesised in 1912, methcathinone in 1928, and mephedrone in 1929. Cathinone is chemically similar to ephedrine, cathine, methcathinone and other amphetamines.

Legal highs generally comprise cathinone stimulants and synthetic cannabinoids. Hallucinogenic agents such as salvia divinorum are also included, the latter sometimes described as herbal ecstasy. Synthetic amphetamines are not regarded as hallucinogenic, though hallucinations are experienced by some users.

Thus, the term ‘designer drugs‘ covers an array of substances which are used recreationally, are not controlled under the Misuse of Drugs Act (1971), are not licensed for ‘legal’ use, and are not regulated under the Medicines Act (1968). They are chemicals produced by tweaking or altering the molecular structure of previous well-known psychoactive agents. By stating they are ‘not for human consumption’, or are just ‘bath salts’, they can be sold legally. Hundreds of such substances are now available, reflecting the ease at which chemists can produce them.

Availability and Consumption

The World Drug Report (available on the Internet) produced annually by the UN Office on Drugs and Crime (UNODC), provides information on the worldwide manufacture and marketing of illegal drugs. The 2013 report highlights a striking rise in the availability of new substances. Part of the challenge lies in their variety - some are derived from plants, for instance, the mint plant Salvia divinorum, native to Mexico, with synthetic cathinones and cannabinoids also being major contributors in other countries.

Ease of synthesis, low cost, and resourceful marketing have contributed to the problem. Information provided via the internet, combined with minimal difficulty in the manufacture and transport from distant regions, together with lax legal enforcement, creates an ideal opportunity for legal highs to flourish. The low cost is particularly attractive though ironically legal highs probably cost more these days: for example, 1g of mephedrone costs about £16.00 more than when legislation was introduced in 2010. On the other hand MDAI (methylenedioxy-2-aminoindane), a legal stimulant and club drug which is snorted or bombed, costs about half the price of cocaine (£20 per gm). It is sometimes cheaper to buy legal highs over the internet than from a drug dealer. Part of the increase in use of legal highs may be a result of decreasing purity of other ‘buzz’ drugs such as cocaine and MDMA.As with other illegal drugs regulatory measures drive the drugs ‘underground’ and into the hands of drug dealers and the price then varies with the purity of the drug and its ease of manufacture and availability.

Some users will revert to taking an illegal drug when the legal alternative is prohibited. There is also a certain curiosity to experiment with new drugs. Even so, to keep things in perspective, consumption of more harmful familiar illegal drugs (for example, cocaine, amphetamines) has not abated, with over 315 million people worldwide thought to be using them. More worrying is that millions of individuals inject more harmful drugs such as opiates with resultant increased rates of HIV, hepatitis B and hepatitis C infection. Readers are also likely to be aware of the violence and deaths associated with drug manufacturing and supplying within countries such as Latin America.

Government Control

The Medicines Act 1968 (UK) governs the control of medicines for human and veterinary use. It defines three categories of medicines: a) prescription only medicines (POM), available solely from a pharmacist and requiring an appropriate practitioner to issue, b) pharmacy medicines (P), available only from a pharmacist, without the need for a prescription, and c) general sales list (GSL) meaning medicines bought without a prescription. The Medicines Act 1968was set up to protect patients from unscrupulous suppliers of medicines. Safeguarding the public from illegal medicines or any inaccurate and misleading labelling of medicines isparamount. However, manufacturers have managed to sell legal highs by passing them off as bath salts or research chemicals.

Phenylalkylamines analogues such as amphetamine are widely misused and because of their simple structure hundreds of amphetamine analogues have been introduced for decades. This is the reason why so many legal highs are available. Amphetamine (phenylisopropolamine), a familiar central nervous system (CNS) stimulant, has effects which last for several hours after oral intake. Methamphetamine is closely related to amphetamine and ephedrine (a mixed-acting sympathomimetic). Ephedrine and pseudoephedrine (often used for relief of nasal congestion) undergo reduction to methamphetamine, or oxidation to methcathinone. As with methamphetamines, methcathinones can be readily ‘cooked’ in the laboratory and hence the term ‘synthetic’.

Background biochemistry

Morphine, the most abundant opiate alkaloid found in the poppy plant, papaver somniferum, was first isolated in 1804. The actual term alkaloid is derived from "alkaloide" introduced in 1819 by the German chemist Carl Friedrich Wilhelm Meisner, from the Latin root ‘alkali’, and the Arabic word al-qalwī meaning "ashes of plants".

Alkaloids are a group of naturally occurring organic nitrogen-containing bases, a base being a substance with a pH above 7 which turns red litmus paper blue. They include related compounds with neutral and even weakly acidic properties and more than 3,000 different types have been identified. In addition to nitrogen, hydrogen and carbon, most alkaloids contain oxygen, sulfur, and to a lesser extent, chlorine, bromine, and phosphorus. Generally, an alkaloid contains at least one nitrogen atom in an amine-type structure, i.e. one derived from ammonia (NH₃) replacing the hydrogen atoms with hydrocarbons, for example, CH₃ or CH₂. Alkaloids generally are weak bases and some act as acid or base (amphoteric).

Alkaloids are produced primarily by flowering plants and organisms such as bacteria, fungi, and animals. Several alkaloids may be extracted from one plant.They can be purified from crude extracts by acid-base extraction and tend to have a bitter taste. Those containing a ring system are known as indole alkaloids (for example, terpenoids and steroids). Some are named after the biological species from which they are derived (morphine from the poppy plant Papaver somniferum, cocaine from erythroxolon coca, and so on). Other common examples include psilocin, caffeine, nicotine, vincristine, reserpine, atropine, quinidine, ephedrine,strychnine and quinine. Atropine is the tropane alkaloid isolated from the deadlynightshade plant Atropa belladonna, and strychnine is derived from the seeds of the Strychnos nux-vomica tree. Caffeine, cocaine, codeine (methylmorphine) and nicotine are water-soluble alkaloids. Morphine and yohimbine are highly water-soluble. Other alkaloids dissolve poorly in water yet readily in organic solvents such as chloroform or ether. The biological precursors of most alkaloids are amino acids, such as phenylalanine, tyrosine, tryptophan, histidine, and aspartic acid, among others. ¹

How are they used?

The synthetic cathinones (usually mephedrone and methylone, or M-Cats) are most commonly used intranasally (insufflated) or ingested. “Bombing” is a method of ingestion whereby mephedrone powder is wrapped in cigarette paper and swallowed. Because sniffing the drug may cause nasal burns users will often resort to ‘bombing’. “Keying” is the practice of dipping a key into powder and then insufflating, with approximately five to eight “keys” per gram. Rectal administration, gingival delivery, inhalation, intramuscular and intravenous injection have also been described. Multiple concomitant routes of administration are reported. Self-reported doses range from a few milligrams to over 1 g of powder. A typical dose of mephedrone would be 100-200mg every 1-2 hours.

Users cannot be certain of the actual contents or indeed of the purity of the drug, therefore actual dosage and exposure is highly variable. For example, when MDAI (methylenedioxy-2-aminoindane) known as Sparkle (a granular, brownish powder) is snorted or bombed, it has an effect similar to ecstasy causing mood enhancement and hallucinations. Onset of action is usually within one hour and the effects are then almost immediate, perhaps a minute or so. The high lasts about six hours with a peak of two hours. It may cause hyperthermia, paranoid ideation and panic attacks.²

Cathinone is a naturally-occurring beta-ketone amphetamine analogue found in the leaves of the khat plant. Other synthetic cathinones such as methcathinone and MDVP (methylenedioxypyrovalerone) produce similar effects. Beta-ketone refers to the possession of a ketone group in the beta position of the aminoalkyl chain attached to the main molecular methylenedioxyphenyl ring.

Synthetic cannabinoids share some functional similarities with Δ9-tetrahydrocannabinol (THC), the active principle of cannabis. Like THC, they can have sedative, depressant and hallucinogenic effects. They have been detected in herbal smoking mixtures such as ‘Spice’ as well as resins that mimic cannabis resin.

Khat (Catha edulis)

Some knowledge of this plant is necessary in order to explain the background to many of the synthetic designer drugs. Khat is an evergreen shrub the leaves of which are chewed for their stimulant properties. An understanding of its chemical composition helps to explain the use of its constituents in the formation of designer drugs. Khat contains more than 40 alkaloids as well as many other compounds. The khat pheylalkylamines consist of cathinone, cathine and norephedrine: these alkaloids are structurally related to amphetamine and noradrenaline. Although similar to methylamphetamine, methcathinone (variously known as Cat, Kat, Qat, Ghat, and Chat) possesses a chemical structure resembling cathinone; its side effects and addictive properties are more potent.

The plant is chewed into a ball and kept in the cheek for a while. When khat leaves dry, cathinone (benzoylethanamine) decomposes within 48 hours leaving behind the milder chemical, cathine (a phenethylamine compound). Therefore, to maintain the potency of the drug, harvesters transport khat by packaging the leaves and stems in plastic bags or wrapping them in banana leaves to preserve moisture. It is common to sprinkle the plant with water or use refrigeration during transportation. Khat is therefore best used within 12-48 hours when the leaves are still moist.

Catha edulis is a flowering plant (one that produces seeds) native to the Horn of Africa (Eritrea, Djibouti, Ethiopia and Somalia) and the Arabian Peninsula. In these countries chewing the leaves and stalks is a social custom dating back thousands of years. It may take 7-8 years for the shrub to reach its full height (6-12 feet or more). Globally it is estimated that some 10 million males (usually) use khat on a daily basis.

Cathaedulis leaves containa beta-ketone amphetamine analogue. Ketones contain a carbonyl group (C=O) bonded to two other carbon atoms. Phenylalkylamines (derived from phenethylamine) are often termed “bk-amphetamines” for the beta-ketone moiety.

The principal active components in khat are cathinone and cathine. By chewing khat these substances are secreted into saliva. The effects are similar to amphetamine though less potent. Psychological dependence does occur in some though generally khat is not addictive. It is freely available in many countries and its production, sale and consumption are legal, including the Horn of Africa. In the Arab Peninsula it is known as Arabian tea and in South Africa it is referred to as Bushman’s tea.

Although its stimulant effect was originally attributed to cathine, extracts from fresh leaves of khat were shown to contain cathinone, isolated in 1975 and its properties recognized in 1978. Cathinone is not very stable and breaks down to produce cathine and norephedrine which belong to the phenylpropanolamine family, a subset of the phenethylamines and the catecholamines adrenaline and noradrenaline.

When the leaves are chewed the active ingredients are absorbed through the oral and gastric mucous membranes. The action of cathine and cathinone on the reuptake of adrenaline and noradrenaline results in the wakefulness associated with amphetamine derivatives. The effects of cathinone peak after 30 minutes, with nearly 98% of the substance metabolized by the liver into noradrenaline. Cathine has a half-life of about three hours in humans. Typically, an individual consumes 100–200 g of khat leaves (one bundle) in a session, and its effects last for several hours.

Symptoms are rather similar to the ingestion of strong coffee or amphetamines, for example, overtalkativeness and hyperactivity. The effects of oral cathinone occur more rapidly than those of amphetamine, 15 minutes compared to 30 minutes respectively. Khat causes constipation, dilated pupils (mydriasis), tachycardia and increased blood pressure, reflecting the sympathomimetic effects of the drug. Withdrawal symptoms, as would be expected, include mild depression and irritability, lethargy, rebound anxiety causing nightmares, tremulousness and loss of appetite. Long-term use may cause hepatic dysfunction, a permanent greenish tinge darkening of the teeth, and diminished libido. Rarely, dilated cardiomyopathy and myocardial infarction result from chronic use. ³

Mephedrone

Mephedrone (‘meow meow’) is a synthetic stimulant chemically related to cathinone, the psychoactive substance present in the khat plant. It is usually sold as a white crystalline or off-white-yellow powder (as a hydrochloride salt) for about £10 per gram. Consumption is usually oral or intranasal and rarely, by injection. Sellers avoid attracting the attention of regulatory bodies by labelling the substance “not for human consumption,” which means that no advice on safer use and dosing is provided.⁴

In one study the most commonly seen drug class were piperazines, followed by the cathinones, with significant variation in the content in one quarter of these compounds. The authors stated that it was relatively easy to purchase a number of legal highs from different Internet suppliers, though there times when not all of the products were available leading to the problem of users buying different active drugs to those they are used to, raising the prospect of potential toxicity to unknown agents.⁵A cross-sectional survey of 947 of mephedrone users found it to be the sixth most frequently used drug in the previous month after tobacco, alcohol, cannabis, cocaine and MDMA. Users typically were young males; 15% reported using weekly or more frequently; nearly 50% used between 0.5 and 1g during a typical session; intranasal use was the most common route of use (70%). Almost 55% of those who used cocaine reported that the ‘high’ obtained with mephedrone was better: intranasal use was also more likely addictive than oral use. Mephedrone appears to be the most widely abused synthetic cathinone in Europe, in contrast to the USA where MDVP and methylone are the most frequently abused. ^{6 7}

Classification of mephedrone has had a limited effect on controlling its availability and use. Before the introduction of the legislation users generally obtained it via the internet. Now it is bought from street dealers, on average at double the price. Mephedrone was defined as a Class B drug under the Misuse of Drugs Act (1971) in the UK in April 2010. ⁴

Mephedrone produces similar effects to ecstasy, amphetamines and cocaine. It is detected in 20% of ecstasy tablets. It simulates the release of and inhibits the reuptake of monoamine neurotransmitters. The onset of psychoactive effects after insufflation is usually 10–20 minutes with an expected duration of effect of 1–2 hours; after oral ingestion onset is about 15–45 minutes with duration of 2–4 hours, and intravenous users report symptoms peaking at 10–15 minutes with a 30-minute duration of the desired effect.

Mephedrone users report that it has a better quality high than cocaine. It is speculated that mephedrone’s popularity reflects dissatisfaction with the purity and consistency of available cocaine and ecstasy. Concerns are also raised when it is considered that mephedrone is readily available from street dealers and may be taken by young people who have little previous experience of drug use.

Blood or plasma mephedrone concentrations are expected to be in a range of 50–100 μg/l in persons using the drug recreationally, >100 μg/l in intoxicated patients and >500 μg/l in victims of acute overdose.

Mephedroneinduces a greater increase in dopamine than serotonin release whereas MDMA (‘ecstasy’) induces a huge increase in serotonin with an insignificant rise in dopamine. Amphetamine results in a surge in dopamine release with an insignificant increase in serotonin. Mephedrone, amphetamine, and MDMA have decay values of 25, 50 and 300 minutes respectively. Therefore, the rapid rise and fall of dopamine levels could explain the addictive properties of mephedrone in some users. The effects are often described as somewhere between ecstasy and cocaine. As with cocaine, the ‘high’ generally lasts around an hour before wearing off. Furthermore, prolonged high –dose use of the substances can produce long-lasting neurotransmitter deficits in humans. ^{8 9}

According to Mixmag (the online drug-use clubbing survey magazine for the UK) published in March 2012, 42% of clubbers had tried mephedrone the drug, and 34% had taken it in the last month. Some 30% of mephedrone users had reported using more ecstasy since the ban came into effect, while 19% reported using more cocaine. Blood or plasma mephedrone concentrations are expected to be in a range of 50–100 μg/l in persons using the drug recreationally, >100 μg/l in intoxicated patients and >500 μg/l in victims of acute overdose.

In 2011, Mixmag and the Guardian newspaper which draws on previous Mixmag surveys collected 15,500 responses from around the world, mostly the United Kingdom. In 2010/11, reported levels of use of mephedrone in the last year and last month were three times higher among clubbers (30 % and 13 %) than non-clubbers (10 % and 3 %).

Mephedronepredictably, causes increased alertness, restlessness, euphoria, excitement, the urge to talk, openness, time rushes, hot flushes, increased libido and elation. Hyperhidrosis, headache, palpitations, a Raynaud–type syndrome, and nausea are other relatively common unpleasant effects. Dizziness, hallucinations, panic attacks, and psychosis may occur. Other physical symptoms include dry mouth, blurred vision, and epistaxis. Symptoms of intoxication include agitation, aggression, violence, seizures and hyperthermia. Fatigue and insomnia are common residual effects. Mephedrone is generally used by nasal insufflation or ingestion of powder, liquid, capsule or tablets. The majority of users source mephedrone from street level dealers.¹⁰ Mephedrone induces strong feelings of craving in most users. If the unstable ecstasy market situation persists, the potential of mephedrone to substitute for MDMA might be substantial. Mephedrone, sold as ecstasy, is therefore more likely to be a cause for concern in the future.

Bath salts

This is the street name for substances which contain synthetic cathinone stimulants, such as methylenedioxypyrovalerone (MDPV) and mephedrone.¹¹Bath salts components act synergistically at the dopamine transporter site and enhanced dopamine transmission may increase the potential for abuse. MDPV is consumed with other illicit drugs of abuse. It is the primary ingredient in "bath salts." Being a synthetic, cathinone-derivative it produces a high similar to cocaine or methamphetamine. It can be administered orally, by nasal insufflation, smoking, intravenously/intramuscularly, or per rectum, and intoxication lasts many hours.

MDPV may cause cardiac problems and disturbance of perception. During the withdrawal period after MDPV use, bone and muscle pain, and visual disturbances may occur. In the metabolism of MDPV, the most important catalyst is the CYP2C19 isoenzyme; the CYP1A2 and the CYP2D6 isoenzymes also play a role. The formed catechols are conjugated with either glucuronic acid or sulphate.

These compounds are not true bath salts in the traditional sense of household products. Cathinone is an amphetamine-like stimulant found naturally in the khat plant, described in more detail below. MDPV is much more potent than cocaine and its effect is longer lasting.¹²

Because of the sympathomimetic activity side effects are predictable and include cardiac arrhythmias, hypertension, arrhythmias, and hyperthermia. Chest pain, myocardial infarction, sweating, rhabdomyolysis, seizures, stroke, cerebral oedema, cardiorespiratory collapse, and rarely, death, have been reported. Psychiatric manifestations include hypersomnia, panic attacks, agitation, paranoia, suicidal ideation, self-mutilation, and aggressive behaviour.

The mode of action is thought to be the result of disruption and interference with central monoamine systems. In other words, synthetic cathinones increase extracellular monoamines by blocking transporter reuptake and increasing presynaptic neurotransmitter release. The dopamine (DA) transporter (DAT) and serotonin (5-HT) transporter (SERT) tightly regulate the amount of neurotransmitters within the synaptic cleft. Monoamine release also may be driven by presynaptic input from cholinergic or glutaminergic systems.^{12 7}

Psychoactive bath salts are sold as tablets, capsules, or powder and purchased in places such as tobacco and convenience stores, gas stations, head shops, and the Internet. Bath salts may mimic cocaine, lysergic acid diethylamide (LSD), methamphetamine, or MDMA. The most common bath salts are the cathinone derivatives MDPV, mephedrone and methylone. The drugs have the potential for addiction because they cause intense stimulation, euphoria, elevated mood, and a pleasurable "rush". ^{13 14}

In the United Kingdom (UK) to avoid being controlled by the Medicines Act, legal highs are sometimes described as bath salts, fertilizer (plant food), or incense, even though they have never been used for these purposes. In other words, legal highs are not covered by current drugs laws yet are used by individuals in the same way as illegal drugs such as cocaine or cannabis. The easy availability of legal highs marketed as "bath salts", ‘incense’ and ‘plant foods’, with the added proviso that they are not to be consumed by humans allows the drugs to circumvent current legislation. When legislation is changed the molecular structure is easily altered to produce a new legal high.

Synthetic cannabinoids

Marketed as ‘incense’ and labeled “not for human consumption”, these drugs were increasingly popular with students and young adults being initially legal and easily available from stores, online, head shops (outlets selling drug paraphernalia/counterculture magazines) and petrol stations. The structure of synthetic cannabinoids does not resemble that of tetrahydrocannabinol (THC] contained in marijuana or hashish, yet the drugs affect individuals in the same manner and are much more potent. Synthetic cannabinoids are sold under countless names such as ‘Mr Nice Guy,’ ‘Spice’, ‘Sabbaba’ and ‘Lemon Grass’, to name a few. Spice is a designer drug derived from herbs sprayed with synthetic chemicals which mimic the effects of cannabis. The ingredients are thus similar to but not identical to THC. Synthetic cannabis can precipitate psychosis, especially in individuals with a previous history and a chronic psychotic disorder may persist in some vulnerable patients.

A great variety of synthetic cannabinoids, most often cannabicyclohexanol, are used in an attempt to avoid prosecution. Some are sold in 'herbal' smoking mixtures and the latter have been found on occasion not to contain any synthetic cannabinoids at all. Cannabicyclohexanol is a cannabinoid receptor agonist drug. It has been sold under various brands such as Black Mamba, Bombay Blue, Fake Weed, Genie, Bliss, Blaze, Yucatan Fire. Spice products sometimes sold as “incense,” more closely resemble potpourri. Although Spice is usually smoked, sometimes individuals mix it with cannabis or prepare a herbal infusion for drinking.

To create the herbal products, synthetic cannabimimetics are dissolved in an organic solvent (e.g. acetone) and the resulting solution is sprayed on plant material. The doped plant material is then dried and smoked in a similar fashion to actual cannabis. Spice products typically have a pleasurable smell and taste. They are often referred to as herbal or legal highs because of their legal status and ‘natural’ herbal make-up. They are distributed in the form of dried leaves or resin, and powder, and are sold without age restriction in metal-foil sachets, usually containing 3 g of vegetable matter, to which one or more of the synthetic cannabinoids have been added. Spice is typically smoked, using a pipe or by rolling in a cigarette paper, and can also be ingested as an infusion, or inhaled.^{15 16}

Drugs of the 2C family (phenethylamines containing methoxy groups attached to a benzene ring) have hallucinogenic and stimulant effects. The term ‘2C’^' refers to the 2 carbon atoms between the benzene ring and the amino group in these compounds. The effects are a cross between MDMA and LSD. They are relatively new to the market and not widely available in the UK. An excited delirium presentation seems to be consistent in deaths attributed to 2C drugs and at least five deaths have been reported in the literature in patients intoxicated with 2C drugs. One agent known as 2C-1 or Smiles, which first appeared in 2003,has more potent effects than MDMA and LSD. Users report an intense energy with vivid visual and auditory hallucinations lasting hours to days.^. Patients may exhibit symptoms consistent with serotonin toxicity. Doctors need to be vigilant as synthetic drugs do not show up on routine testing. Treatment of 2C intoxication is primarily supportive.¹⁷

Despite widespread Internet availability, many of these drugs remain unfamiliar to doctors and yet ‘bath salts’, have resulted in nationwide emergency department visits for severe agitation, sympathomimetic toxicity, and death. As with other illicit substances designer drugs may compromise cardiac function causing hypertension and tachycardia and users who inject run the well-known risks of contracting hepatitis C or HIV, thrombophlebitis and embolus formation.

Methoxetamine

Methoxetamine (also known as ‘mexxy’) is available on the Internet and marketed as ‘legal ketamine.’ It is an arylcyclohexylamine chemically related to ketamine and PCP (phencyclidine). Methoxetamine is longer acting and more potent than ketamine. The drug, a white powder, is usually taken sublingually, snorted, ‘bombed’, or injected intramuscularly. Doses are typically between 5mg-90mg orally. After snorting the drug it may take 30-90 minutes for its effects to become apparent. When injected the onset of action is usually within five to ten minutes. The overall duration of effect is within the range of 1–3 hours, sometimes longer. The drug induces feelings of detachment (dissociative state), paranoid symptoms, visual hallucinations, restlessness and increased energy in some. Other reported symptoms include confusion, catatonia, depression, tachycardia and hypertension. Methoxetamine is now a Class B drug under the Misuse of Drugs Act.^{18 19}

Piperazine derivatives

The piperazine derivatives, a class of amphetamine-like compounds that includes BZP (benzylpiperazine) and TFMPP (trifluoromethylphenylpiperazine) are making a comeback as "legal ecstasy." Often perceived as safe by the public, adverse effects may range from minimal to life-threatening. Co-ingestion of BZP and TFMPP causes increased action of dopamine and serotonin, similar to MDMA. Severe symptoms include seizures, hyperthermia, hyponatremia, dystonic reactions, rhabdomyolysis, renal failure, metabolic acidosis, DIC, and respiratory failure. ²⁰ Over the last few years piperazine derivatives are being sold as ecstasy pills, or under the names of “Frenzy”, “Bliss”, “Charge”, “Herbal ecstasy”, “A2”, “Legal X” and “Legal E”. Although piperazine designer drugs enjoy a market reputation of being safe, they may cause distorted perceptions after ingestion. There are several reports of toxic symptoms experienced by users after drug intake.The piperazinic compounds are derived from piperazine, a cyclic molecule containing two opposite nitrogen atoms and four carbon atoms distributed between the two and were originally used as anti-helminthic agents in the 1950s. Designer drugs of this class can be divided into the benzylpiperazines such as benzylpiperazine (BZP) and its methylenedioxy analogue methylenedioxybenzylpiperazine (MDBP), and phenylpiperazines such as chlorophenylpiperazine (CPP), trifluoromethylphenylpiperazine (TFMPP), and methoxyphenylpiperazine (MeOPP). A third group includes the thienylmethylpiperazines. Chlorophenylpiperazine is an active metabolite of drugs such as trazodone, and nefazodone used as antidepressants. A survey in the UK found that piperazines are among the most common active drugs in tablets purchased from internet supplier sites.Piperazine-derived compounds are therefore emerging designer drugs, whose abuse has increased remarkably worldwide.²¹

Naphyrone

Naphyrone(naphthylpyrovalerone) or NRG-1 (or Energy1) is a cathinone derivative available to buy on a number of websites and is gaining popularity. It is sold as an alternative to mephedrone. Belonging to the designer drugs class, it is similar in structure to pyrovalerone, a monoamine uptake inhibitor and as it is somewhat similar to other cathinone derivatives it has the potential to produce anxiety, paranoia, and cardiovascular side effects. Two products, both sold as NRG-2 from different internet suppliers, were found to contain the banned substituted cathinones - 4-methylethcathinone (4-MEC) and 4-methylmethcathinone (4-MMC), the latter being present in much smaller quantities. Although sold as research chemicals and labelled 'not for human consumption', they are essentially legal highs and are available online. ^{22 23}

Table 2: Some commonly used psychoactive substances

Discussion

New designer drugs have increased in popularity over the past several years because of their euphoric effects. Understanding the pharmacology and toxicology of these agents is essential in order to provide the best medical care for patients. They are all potentially dangerous. For example, an excited delirium presentation seems to be consistent amongst deaths attributed to 2C drugs.

From the above description it can be seen that synthetic drugs fall into three broad categories: synthetic cathinones (bath salts), synthetic cannabinoids (spice or incense), and amphetamine-like drugs (methamphetamine, ephedrine, MDMA). Cathinones being related to the amphetamine family will cause dilated pupils, hypertension, hyperventilation, paranoia, agitation, hyperthermia, tremors and seizures. Many countries have made certain cathinones illegal, for example, mephedrone, methylone and MDPV. Indeed, the robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations. Furthermore, pyrovalerone is much more potent than cocaine at inhibiting the uptake of dopamine and norepinephrine.

Methcathinone was previously used in Russia as an antidepressant, also known as “Cat” and “Jeff” when used recreationally. Nowadays the drugs are sold as bath salts, plant food, insecticides, chicken feed additives, or research chemicals with names such as like NRG (Energy) and meow, meow. Bath salts are water-soluble, usually inorganic, solid products designed to be added to water during bathing. Numerous nicknames are used to describe them including Ivory Wave, Purple Wave, Red Dove, Zoom, Bloom, Cloud Nine, Ocean Snow, Lunar Wave, Vanilla Sky, White Lightning, and Hurricane Charlie.

Although ‘legal highs’ are commonly referred to as bath salts they are not Epsom salts (magnesium sulphate) or other water softeners within the usual meaning. In many cases the chemical ingredients are changed without the consumer knowing, making risks unpredictable. Some legal highs contain active ingredients controlled under the Misuse of Drugs Act 1971 (UK). Therefore any individual found in possession of these products would be liable to prosecution and the associated penalties, even if unaware that he/she has purchased a controlled drug. However, claiming a product to be "not intended for human consumption" can potentially circumvent the entire legal process. Drug designers are already showing skilful exploitation of the law and remain far ahead of criminalization efforts. Furthermore, the irony of prohibition is that the supply and slump in the market for cocaine and ecstasy in 2009 led to individuals resorting to untried and untested substances that are now easily available online. ^{24 25}

Synthetic cathinones are mostly excreted via the urine and can be measured via gas or liquid chromatography-mass spectrometry in the blood, urine and stomach contents. They can also be analysed in hair. Unlike traditional cosmetic bath salts, which are packaged and sold for adding to bath water for soaking and cleaning, synthetic designer drugs sold as "bath salts" have no legitimate use for bathing and are intended for abuse. Baths salts contain one or more synthetic derivatives of the naturally-occurring stimulant cathinone. Low doses produce euphoria and increase alertness, but high doses or chronic use may cause serious adverse effects.²⁶

Treatment

Treatment should be tailored to the specific drug of abuse. Medical and psychological needs require examining. Generally, treatment uses a combination of counselling and medication to reduce the need or desire (craving) for the drug and give the person the skills to refrain from future drug use. Other treatments might include cognitive behavioural therapy, detox, and relapse prevention techniques.

Supportive care is the mainstay of treatment for untoward serious side effects. Sedation with benzodiazepines is indicated for agitation, seizures, tachycardia, and hypertension. Extreme hypertension that persists despite benzodiazepines may be treated with vasodilators. Beta blockers should be avoided due to the potential to cause unopposed alpha-adrenergic stimulation, worsening the hypertension. Significant hyperthermia may require passive or active cooling. All moderately to severe symptomatic patients should have an electrocardiogram (ECG), be placed on a cardiac monitor, and receive serial temperature checks. Electrolytes, liver function tests, cardiac enzymes creatine, and toxicology should be carried out. Asymptomatic patients with no other suspected ingested drugs or psychiatric symptoms generally may be discharged.

Prevention

Banning legal highs is probably futile because it is impossible to keep up with newer drugs because they are synthesized as soon as the ‘illegal’ drug becomes banned. Some would argue that arresting users creates more harm for individuals, their families and society, as they are then caught up in the criminal system. Others may argue that ‘legal highs’ are not generally harmful and not as dangerous as opiates or their derivatives, or indeed alcohol. It might be more worthwhile making legal highs ‘uncool’, much in the same way that cigarette consumption is now frowned upon. However, it would require a great deal of public money to subsidise such an advertising venture.

Users of legal highs need to be made aware that such drugs purchased on-line may contain illegal substances and therefore may render them subject to prosecution if found in possession. ²⁷

Pre-school family based programmes, and programmes involving the school and community, motivational interviewing for adolescents, and individual programmes, may be beneficial in reducing drug use and other harmful outcomes. Importantly, none of these approaches focus exclusively on particular substances or groups of substances, and although there have been relatively few investigations of intervention processes they most likely work by targeting a number of important precursors of drug use behaviour.²⁸

Preventing designer drug abuse begins with understanding the warning signs of addiction which in many respects are similar to alcohol or more common street drugs.

Club drugs are now widely available and their harmful effects are increasingly becoming more evident. Their effects are unpredictable as they are often ‘contaminated’ with other harmful substances. It is unlikely that legislation will have a meaningful impact. Increasing public awareness about these drugs is paramount, and medical and nursing staff should consider intoxication in those patients who present with agitation and psychosis who have no previous history of mental health problems.

Pharmacists are in a pivotal position to observe changes in patterns of drug use and report worrying trends to health care practitioners. Counselling for young people especially and prevention programmes based in schools could prove useful in pointing out the dangers of these drugs to teenagers. Health care professional too should endeavour to keep up with recent information on these substances by attending hospital-based lectures or conferences as part of continuing professional education.

Urine drug testing will generally be unhelpful as many club drugs are undetectable on standard urine drug screens.²⁹ Mental health staff should enquire about club drugs as part of routine drug and alcohol assessment and be aware that these patients may not fit the stereotype of a drug misuser.

It all began when she was sixteen.

She started getting, increasingly,

Worried about her weight.

All day she dreamt of getting slim, getting lean.

Her days revolved around counting calories.

She made every effort to avoid fattening food, 

To survive on soup, toasts, coffee and berries.

Her fear of being judged, fat and ugly, was overwhelming.

Her life revolved around specific chores

Of excessive exercises, 

Of inducing vomiting, of taking 

Laxatives. All hidden from her family and friends.

Like a tree in the winter, bereft 

Of life, bereft of glow, she lost 

Her every feature, every playfulness,

That made her beautiful, that made her desirable.

She was slowly withering, like crops 

In a drought, until her family 

Alarmed her to see a doctor. A timely 

Intervention, timely support, raised

The hopes of a new dawn

The hopes of her recovery.

Case history

A 46 year-old man presented to the Emergency department with chest pain and collapse, associated with loss of consciousness lasting several minutes. He had no significant past medical history and he had no risk factors for coronary artery disease. However, he did note a similar episode of collapse and loss of consciousness one year prior for which he did not seek medical attention. There was no known family history of heart disease or sudden death.

On examination he was haemodynamically stable with a blood pressure of 130/80 mmHg and heart rate of 85 beats per minute. Jugular venous pressure was measured at 2cm above the sternal angle and heart sounds were normal with no added sounds. His oxygen saturation was 98% on air and chest was clear to auscultation. Chest X-Ray demonstrated clear lung fields and laboratory investigations, including electrolytes and cardiac troponin T were within normal limits. Echocardiography showed a structurally normal heart. Figure 1 shows his 12-lead electrocardiogram (ECG) on admission.

Figure 1 – 12 lead ECG on admission

Questions

1. What is the likely diagnosis based on the clinical presentation and ECG findings?

2. What life-threatening arrhythmias can arise from this condition?

3. What is the pathophysiology of this condition?

4. How is the diagnosis of this condition made?

5. What treatment options are available for patients with this condition?

Answers

1. What is the likely diagnosis based on the clinical presentation and ECG findings?

Short answer

Brugada syndrome

Long answer

The ECG shows coved Type 1 ST segment elevation in keeping with a diagnosis of Brugada syndrome.

First described in 1992, Brugada syndrome is a primary cardiac electrical disease or channelopathy that is accompanied a structurally normal heart and carries an association with sudden cardiac death¹.

Presentation often occurs in the third or fourth decades of life, with a male preponderance of 8:1, however sudden cardiac death due to Brugada syndrome has also been seen in patients at the extremes of age. It is estimated that it accounts for up to 20% of all sudden cardiac deaths in patients without structural heart disease, ischaemia or electrolyte abnormalities². It is most commonly seen in south-east Asia, especially Thailand, where its incidence is around 1%, and is much less common in western countries¹.

2. What life-threatening arrhythmias can arise from this condition?

Short answer

Brugada syndrome is associated with increased risk of ventricular tachycardia (VT), often polymorphic, and ventricular fibrillation (VF).

Long answer

Brugada syndrome often manifests clinically in the form of syncope or sudden cardiac death. It is most commonly associated with polymorphic VT and VF, which may or may not terminate spontaneously. There are a large proportion of patients with Brugada syndrome who never experience any symptoms and indeed, may not ever even be identified as having the condition, unless they are found to have incidental ECG abnormalities as part of routine medical testing or are under investigation for another problem³.

3. What is the pathophysiology of this condition?

Short answer

Brugada syndrome is understood as a genetic cardiac channelopathy, a disorder produced by the dysfunction of a cardiac ion channel participating in the action potential which can result in electrical change favouring the development of arrhythmias. Inheritance of the condition occurs via an autosomal dominant mode of transmission with incomplete penetrance⁴.

Long answer

Brugada syndrome is a genetic disorder, with a loss-of-function mutation of the SCN5A gene implicated in about 30% of sufferers. This gene codes for the α-subunit of the cardiac sodium channel. Other mutations of sodium and calcium channels have also been found. In inherited cases, the gene is passed in an autosomal dominant fashion, though sporadic mutations are also seen.

There is increased susceptibility to ventricular arrhythmias, because of altered depolarisation within the right ventricle. In SCN5A mutations, the defect in sodium channels leads to decrease in the sodium current and a shortening of the cardiac action potential by blunting phase 0 depolarisation. Potassium channels are also affected, with an increased number of transient outward potassium channel currents. This imbalance in the myocytes between sodium and potassium concentrations means the overall effect is to shorten the refractory period, making the myocytes more prone to re-entrant circuits, leading to the development of VT and degeneration to VF^2,5.

4. How is the diagnosis of this condition made?

Short answer

Brugada syndrome is characterised by electrocardiographic changes demonstrating coved ST segment elevation in the right precordial leads.

Long answer

Electrocardiographic abnormalities constitute the hallmark of Brugada syndrome. There are three different ECG patterns and in all three types, the ECG shows ≥2mm J point (junction between the termination of QRS complex and beginning of ST segment) elevation and a characteristically shaped ST segment in the right precordial leads⁶.

Type I has a ‘coved’ pattern ST segment elevation ≥2mm, with a descending terminal portion in at least one right precordial lead.

Type II has a ‘saddle-back’ ST segment elevation ≥1mm and has a high elevation in its initial portion.

Type III has either coved or saddleback ST elevation but is less accentuated than types I or II (<1mm).

Although all the 3 patterns can be present in patients with Brugada syndrome, only the presence of a type-1 ECG pattern defines the diagnosis of the condition^2,7. The patterns for type II or III are not diagnostic, and carrying out a Class I anti-arrythmic drug (AAD) test to confirm the diagnosis is recommended. This can be done with AADs such as ajmaline, flecainide or procainamide, though currently ajmaline is preferred due to its higher sensitivity in revealing Brugada type ECG changes¹.

It is worth noting that the resting ECG changes associated with Brugada syndrome (in particular type I) are often transient, and therefore, in someone in whom the diagnosis is suspected, an AAD test may be indicated even if there are no resting spontaneous ECG abnormalities evident⁶.

Differential diagnoses of Brugada syndrome must be approached with care as ST segment elevation is associated with a wide variety of benign and malignant pathophysiologic conditions³.

5. What treatment options are available for patients with this condition?

Short answer

Currently, the implantable cardioverter defibrillator is the only proven effective treatment in the prevention of sudden cardiac death.

Long answer

Management of Brugada syndrome is focused on risk stratification of patients to prevent arrhythmic death in high risk individuals. ICD implantation can prevent sudden cardiac death in these groups¹. Newer devices are now also being used, including the subcutaneous ICD which is implanted in a subcutaneous pocket and does not require any endovascular leads in the heart or access to the central venous circulation⁸.

Pharmacological options are focused on rebalancing the ion channel current active during the early phases of the epicardial action potential in the right ventricle^3,9. Some studies have evaluated the role of quinidine in the treatment of Brugada syndrome and found it to be effective in preventing polymorphic VT and VF in this condition¹⁰. Quinidine has also been proposed as an alternative to ICD implantation in children and infants too young to receive an ICD^11,12.

Data relative to the use of cryosurgical treatments or ablation therapy in Brugada syndrome are very limited at this point in time³.

Patient outcome

The patient underwent successful implantation of a subcutaneous cardioverter defibrillator. Figure 2 and Figure 3 show chest radiographs of the leadless device.

Figure 2 – Chest radiograph (PA view) showing the implanted subcutaneous ICD

Figure 3 – Chest radiograph (lateral view) showing the implanted subcutaneous ICD

INTRODUCTION

Surgery and anaesthesia have traditionally been viewed as expensive, resource-intensive and requiring highly specialized training.¹ This misconception has led to surgery and anaesthesia taking a back seat to public health, maternal and child health, and infectious diseases in global health.² Surgery has also been termed the “neglected stepchild of global health.³These concepts have changed rapidly since it has been found that surgical diseases contribute about 11% to Disability Adjusted Life Years⁴ and therefore would benefit from preventive and public health strategies necessary to achieve the Millennium Development Goals. The realization of the huge public health burden of surgical diseases in low and medium income countries (LMICs), and the fact that surgical services and treatment could be made cost effective, led World Health Organization (WHO) to launch the Global Initiative for Emergency and Essential Surgical Care (GIEESC) in 2005.⁵

The GIEESC is a global forum whose goal is to promote collaboration among diverse groups of stakeholders to strengthen the delivery of surgical services at the primary referral level in LMICs.⁵ Improvements in surgical services at the primary referral level in LMICs will equally require the provision of safe and effective anaesthesia. The provision of safe and effective anaesthesia will need adequately trained human resources and essential health technologies. The surgical and anaesthesia service capacity have generally been very low in sub-Saharan Africa (SSA) as evidenced through surveys conducted in Ethiopia,⁶ Gambia,^7,8 Ghana,^9,10 Liberia,^8,11 Malawi,¹² Nigeria,¹³ Sierra Leone,^8,14 Rwanda,^15,16 Tanzania,^8,17 and Uganda.¹⁸ The survey from Nigeria was conducted among rural private hospitals and was administered to attending members in a conference of the Association of Rural Surgical Practitioners of Nigeria.¹³ This was done using the Personnel, Procedures, Equipment and Supplies (PIPES) survey tool developed by the non-governmental organization Surgeons Overseas (SOS).¹³ This is a tool developed to assess surgical capacity through the workforce, infrastructure, skill, equipment, and supplies of health facilities in LMICs.¹³ The other indicated surveys done in SSA used a comprehensive survey tool designed by the Harvard Humanitarian Initiative. This tool was adapted from the WHO Tool for Situational Analysis to Assess Emergency and Essential Surgical Care as part of an international initiative to assess surgical and anaesthesia capacity in LMICs.

The present survey used a rapid assessment tool known as the Lifebox Hospital Initial Needs Assessment questionnaire with another structured questionnaire to assess anaesthesia services in public hospitals in the Cross River State (CRS) of Nigeria. Lifebox (www.lifebox.org) is a non-profit organization saving lives by improving the safety and quality of surgical care in low-resource countries.¹⁹ Since 2001, Lifebox has trained more than 2000 anaesthesia providers, and more than 4200 pulse oximeters have been supplied to more than 70 low-resource countries thereby closing the operating room pulse oximetry gap in about 15 countries.¹⁹ This organization is supported by the World Federation of Societies of Anaesthesiologists (WFSA), Association of Anaesthetists of Great Britain and Ireland, Harvard School of Public Health and the Brigham and Women’s Hospital in Boston, United States of America.¹⁹ This survey was primarily aimed at the secondary health care facilities which are owned and managed by the CRS Ministry of Health (MOH). This survey audit will identify the anaesthesia providers in CRS, their level of training and retraining as well as equipment available for providing safe anaesthesia and monitoring patients in the peri-operative period. The data will also identify baseline information and gaps in anaesthesia and surgical capacity as a first step for the CRS MOH initiative to improve surgical and anaesthesia services. This information is a stepping-stone for national and international assistance since CRS is a relatively poor state in the Nigerian Federation.

Country and State overview

Nigeria is the most populous African country, located in the West African sub-region with a population of more than 160 million people.²⁰ It is a Federal Republic with 36 states and a Federal Capital Territory. It is politically sub-divided into six geo-political zones: North-Central, North-Eastern, North-Western, South-Eastern, South-South and South-Western. There are 774 Local Government Areas (LGAs) where more than 60% of the population reside. The health care system is divided into three levels: primary, secondary and tertiary. There are public and private health facilities operating at all levels. The primary healthcare facilities (health centres) are managed by the Local Government, the secondary healthcare facilities (general hospitals) are managed by the State Government, while the tertiary facilities (University Teaching Hospitals and Federal Medical Centres) are managed by the Federal Government. Health indicators for Nigeria are among the worst in the world despite the fact that Nigeria is the sixth largest exporter of crude oil. The United Nations Human Development Index ranked Nigeria 156 out of 187 countries.²¹ In particular, Nigeria is one of the five countries contributing more than 50% to the global maternal mortality ratio²² and one of the countries with the highest physician’s and nurse’s emigration to developed countries.²³ Physicians and nurses who remain in Nigeria predominantly practice in urban cities leaving the LGAs, most of them rural with severe shortages in health manpower.

CRS, with approximately 3.2 million population and 20156 square kilometres, is located in the South-South geo-political zone.²⁴ The state has boundaries with the Republic of Cameroon in the East, Benue State in the North, Ebonyi State in the North West and Akwa-Ibom State in the South.²⁴ It is divided into 18 LGAs with 18 general hospitals and 613 primary health centres. There is only one tertiary health facility, the University of Calabar Teaching Hospital (UCTH) located in Calabar, the capital city, which provides specialist care to the entire population. Being a tourism state, the importance of safe anaesthesia as a component of safe surgery cannot be overemphasized.

Physician-anaesthetist, nurse-anaesthetist and surgery training programs in Nigeria

Physicians are trained to be specialist anaesthetists or surgeons in a four-year training program leading to the Fellowship in Anaesthesia (FMCA) or Surgery (FMCS) of the National Postgraduate Medical College of Nigeria (NPMCN) or the Fellowship in Anaesthesia or Surgery (FWACS) of the West African College of Surgeons (WACS). This is after a six-year medical education program in the university leading to the Bachelor of Medicine and Bachelor of Surgery degree, one-year rotatory internship, and one-year of compulsory National Youth Service. Most Fellows, after completion (average time of completion is 7-8 years), work in University Teaching Hospitals and Federal Medical Centres, all located in urban cities. Another training program for doctors designed for primary and secondary healthcare is the Diploma in Anaesthesia (D.A) of the Universities or WACS, which is a 12-month training program. There is no short training program in Surgery.

Nurses are trained as nurse-anaesthetists after 18 months of training in a post-basic nursing program. The basic nursing training program is three-years of training in general nursing, after completing six years of secondary school education. There are now few university degree programs leading to the Bachelor’s degree in Nursing Science (BSN) from the universities. All these nursing training programs lead to certification by the Nursing and Midwifery Council of Nigeria.

Rural-urban practice

Physician-anaesthetists (Fellows and Diplomates), nurse-anaesthetists and consultant surgeons are all concentrated in urban hospitals leaving the rural areas and urban slums with a critical shortage of anaesthetic and surgical workforce. Therefore the majority of the surgical and anaesthetic procedures in rural areas in Nigeria are carried out by government-employed medical officers with almost all anaesthesia being provided by nurse-anaesthetists. In some very remote districts, Community Health Extension Workers (CHEWs) and Community Health Aids with little or no formal training in providing surgical care, are the only health workers available to provide some form of surgical care. The Association of Rural Surgical Practitioners of Nigeria (ARSPON) has been making some effort to address this workforce gap in rural areas by providing short on-the job training for medical officers to enable them to provide safe and affordable surgery to the rural population.¹³ The concept of surgical task-shifting to “non-physician clinicians” to address this rural-urban surgical workforce disparity, as is being officially done in other LMICs of SSA²⁵ is not acceptable in Nigeria.

METHODOLOGY

A standardized questionnaire, the Lifebox Hospital Initial Needs Assessment Survey (Appendix 1) and another structured questionnaire (Appendix 2) was distributed to all 18 general hospitals (secondary health facilities) in CRS. All the general hospitals, which are the first referral hospitals in the districts, perform surgery. The site visit was conducted in April/May 2014. Permission to conduct the site visit was given by the CRS Honorable Commissioner for Health. The hospital surveys did not involve face-to-face interviews with the medical superintendents, hospital matrons or anaesthesia providers. The questionnaires were to be completed by the anaesthesia providers and medical superintendents in each of the hospitals visited. Each completed questionnaire was to be sent to the office of the Honorable Commissioner for Health at the MOH headquarters in Calabar, the capital city. The results are presented in frequency tables and charts.

RESULTS

A total of 16 well-completed questionnaires were received from 18 general hospitals/secondary healthcare facilities visited (88.9 % response rate). Averages of 3 - 53 surgeries are performed monthly in each of the hospitals (Table 1). The common procedures performed include: herniorrhaphy, appendicectomy, caesarean section, myomectomy, prostatectomy and exploratory laparotomy (Table 1). There are no practicing physician anaesthesiologists or surgeons employed by the State MOH except for one visiting consultant anaesthesiologist and five visiting consultant surgeons from the University of Calabar Teaching Hospital (UCTH), at the General Hospital, Calabar, which is located in the capital city of the State (Table 1). There are 13 nurse-anaesthetists distributed unevenly in the 16 hospitals (Table 1). There are no clinical officers cadres in the Nigerian healthcare system. Apart from the nurse-anaesthetists at the General Hospital in Calabar and Dr Lawrence Henshaw Memorial Hospital, also in Calabar, the other nurse-anaesthetists have had no refresher course or in-service training in the past two years. In the 16 general hospitals, the commonest anaesthetic technique used is Total Intravenous Anaesthesia (TIVA) with Ketamine (Table 1).

Table 1 : Summary of audit of anaesthesia services in the 16 district hospitals in Cross River State, April/May2014

GA: General Anaesthesia. ETT: Endotracheal Intubation. C/S: Caesarean Section. CSE: Combined Spinal and Epidural anaesthesia.

Basic anaesthetic equipment such as anaesthetic machines, oxygen cylinders, suction machines, and pulse oximeters were lacking in most of the hospitals visited (Box 1).

The WHO Surgical Safety Checklist Information was administered to the hospitals management team at the Districts Hospital (Box 2). This shows that all the surgical teams had never used the WHO checklist, never received training, and the checklist was not available in the operating rooms, although all surgical personnel would like to receive training on the WHO checklist and pulse oximetry

DISCUSSION

This survey aimed to provide a quick assessment of anaesthesia and surgical services in public hospitals in CRS of Nigeria. The data shows gross and significant shortages in anaesthesia and surgical providers in all 16 general hospitals. There were no consultant anaesthetists, diplomate anaesthetists or consultant surgeons employed in the CRS MOH. There were only 13 nurse-anaesthetists working in the 16 general hospitals, and one visiting consultant anaesthetist and five visiting consultant surgeons at the General Hospital, Calabar, the capital city. In six of the hospitals, there were no nurse-anaesthetists providing care for the surgical procedures being conducted. As it has been reported from the many surveys in SSA.^{6, 18, 26} most of the procedures in all the hospitals are being done by generalist medical doctors and general nurses, many without any postgraduate training in surgery and anaesthesia.

The gross inadequacy of the anaesthetic workforce in this survey represents what is found in many of the 778 LGAs (Districts) in the Federal Republic of Nigeria. This is because many of the LGAs are rural and studies have indicated the general difficulties of most health workers seeking jobs in rural hospitals. The lack of specialist anaesthetists in peripheral hospitals in most of Nigerian Districts therefore requires a re-direction of the training programs for doctors in Nigeria with greater emphasis on the shorter training program design for primary and secondary healthcare levels. Inaddition, annual refresher courses should be made mandatory for nurse-anaesthetists especially for those practicing in rural areas.

A recent review of the met and unmet needs of surgical disease in rural SSA, where district and rural hospitals are the main providers of care, shows a very huge burden.²⁷ An important finding is the discrepancy between surgical care needs and provision.²⁷ Since the majority of the population in SSA reside in rural areas, there is the need to strengthen the surgical services at this level. This is the first of the four recommendations of the Bellagio Essential Surgery Group.²⁸ Many of the surveys using the WHO Situational Analysis Tool have described the lack of capacity in many district hospitals to meet the local surgical and anaesthesia needs.^6-18 One study, using pulse oximeter availability as a measure of operating room resources, showed that between 58.4% and 78.4% of operating rooms in West Africa, East Africa and Central SSA do not have pulse oximeters.²⁹ This finding was also clearly shown by our own rapid survey and assessment. Three important factors have been responsible for these findings. These are lack of resources, lack of manpower and the need for training.²⁷ The need for training to improve the quality of the surgical and anaesthesia providers at the district hospitals is the third recommendation of the Bellagio Essential Surgery Group.²⁸

Training programs and improvement of the facilities at the District Hospital has been shown to increase the number of operations performed.²⁷Also, the presence of a visiting consultant anaesthetist in the District Hospital has been shown to increase the scope of anaesthesia services during the visiting period.³⁰ The visit left more knowledgeable local staff in the care of their patients especially in peri-operative care.³⁰ The need for developing countries in SSA, particularly in Nigeria, to concentrate more on shorter training programs in surgery and anaesthesia at their current level of development has been advocated.^31,32 This has been shown by Sani et al where a 12-month training program for General Practitioners in district hospitals in Niger significantly reduced the number of referrals to the regional and specialist hospital.³³ In many other SSA countries, where gross shortages of medical manpower exist, surgical task shifting has been championed and research has shown that these are cost effective interventions.^{25, 34} This is, however, not acceptable in Nigeria which is Africa’s most populous country with very poor health indicators.

There are some limitations to this study. Firstly, it was a snapshot of anaesthesia and surgical services which did not highlight in detail the eight key areas of surgical and anaesthesia care, as in other surveys. These key areas include: access and availability of hospital services, human resources, physical infrastructures (including availability of water and electricity), surgical and anaesthetic procedures, surgical and anaesthesia outcome, essential equipment availability, NGO and international organizations providing care, and access to essential pharmaceuticals. Secondly, this assessment did not include the only public tertiary hospital in the State and private hospitals. Lastly, this was an initial assessment in preparation for a more detailed survey based on the WHO guidelines when research funds are received.

CONCLUSION AND RECOMMENDATIONS

Therehas been a paradigm shift in global public health and the concept of primary healthcare which has resulted in increased awareness of the importance and contributions of surgical disease to the overall burden of disease especially in LMICs. This rapid survey of anaesthesia services in CRS, one of the 36 states in Nigeria, will serve as a window to inform other Nigerian State governments of the need to increase surgical and anaesthesia capacity and funding in their development agenda. It is therefore recommended that visiting consultant’s services to all the general hospitals in an organized and planned fashion should be highly encouraged. All the anaesthesia caregivers should attend refresher courses at least once every two years. These courses can be arranged locally, or sponsorship provided for attendance of relevant courses by Anaesthesia Trainers within and outside the State. Basic anaesthesia equipment and guidelines as recommended by the Nigerian Society of Anaesthetists (Box 3) must be available and followed to enhance patient safety. It is also recommended that the government should give incentives to medical and nursing staff working in rural areas so that there will be a reversal of the rural- urban shift. The Lifebox global oximetry project is interested in making high quality, low-cost pulse oximeters available in every operating room. Therefore, every secondary care facility in the country should take advantage of this laudable program.

Global Health can be defined as “an area for study, research, and practice that places a priority on improving health and achieving health equity for all people worldwide”. ¹ Article 25 of the 1948 Universal Declaration of Human Rights declares that, “everyone has the right to a standard of living adequate for the health of himself and of his family”. ² Unfortunately, the health disparity between high-income and low-income countries, as well as between individuals within a country, often makes this impossible, leaving many people living in unhealthy settings without sufficient access to care.  

The field of global health is concerned with the health of populations worldwide, focusing on issues that typically have global, political, and economic significance. These health issues usually transcend national boundaries and are best solved through international collaboration. ³ Global health initiatives aim to improve the health and wellbeing of impoverished, vulnerable, and underserved people worldwide. ¹ These initiatives include poverty reduction strategies, disease prevention measures (for HIV/AIDS, malaria, and tuberculosis, for instance), efforts to improve nutrition and food security, policy to raise environmental standards and living conditions, and the promotion of gender equality.  

In 2001, the Commission of the World Health Organization (WHO) recommended to fund global health with 0.1% of GDP. ⁴

The average expenditure per capita for health in low-income countries is estimated at $ 20 per year while that of Western countries is estimated at $ 947. The target to be reached to help out the most disadvantaged countries is $ 44-60 per capita, which would ensure the populations of the poorest countries with the access to essential health services. Directing the 0.1% of the GDP of developed Western countries to the aids for global health would mean closing the gap to reach the target base of $ 44-60 that would allow the saving of 8 million lives a year. ⁴

Despite the good intentions, there is still a marked disparity between the current spending levels and the commitments made by developed countries in a context in which, among other things, the percentage of aid for global health has been in decline for almost all donor countries.

Activists claim that only 10 per cent of global health research is devoted to conditions that account for 90 per cent of the global disease burden – the so-called ‘10/90 Gap’. ⁵ They argue that virtually all diseases prevalent in low income countries are ‘neglected’ and that the pharmaceutical industry has invested almost nothing in research and development for these diseases.

In fact, the WHO acknowledges that there are only three diseases that are genuinely ‘neglected’: African trypanosomiasis, leishmaniosis and Chagas disease. ⁶

A large proportion of illnesses in low-income countries are entirely avoidable or treatable with existing medicines or interventions. Most of the disease burden in low-income countries finds its roots in the consequences of poverty, such as poor nutrition, indoor air pollution and lack of access to proper sanitation and health education. The WHO estimates that diseases associated with poverty account for 45 per cent of the disease burden in the poorest countries. ⁷ However, nearly all of these deaths are either treatable with existing medicines or preventable in the first place.

If treatments exist for the majority of poor countries’ health problems, why then do mortality rates remain so high? Any discussion of this question must address the problem of access to essential medicines, which remains an intractable political and economic problem. According to the WHO, an estimated 30 per cent of the world population lacks regular access to existing drugs, with this figure rising to over 50 per cent in the poorest parts of Africa and Asia. ⁸ And even if drugs are available, weak drug regulation may mean that they are substandard or counterfeit.

Within these populations, it is the poorest socioeconomic groups that disproportionately suffer from a lack of access to existing medicines. ⁹ The implications of this failure of public health policy on global mortality are profound – according to one study, over 10 million children die unnecessarily each year, almost all in low-income or poor areas of middle income countries, mostly from a short list of preventable diseases such as diarrhoea, measles, malaria and causes related to malnutrition. ¹⁰

Many governments fail their populations in this respect by imposing punitive tariffs and taxes on medicines, and by skewing their spending priorities in favour of defence over health. The governments of poor countries hinder the creation of wealth, imposing obstacles in the way of owning and transferring property, imposing unnecessary regulatory barriers on entrepreneurs and businesses, and restricting trade through extortionate tariffs. It is these and other political failures that have left poor populations without the necessary resources to access the medicines that could so easily transform their quality of life.

In conclusion, it appears more and more urgent and necessary to decide where to direct our efforts and investment in research, without prejudice, analyzing all the possible strategies for tackling global health issues, including those standing beyond the current economic paradigm based on the market.

Introduction

Adiponectin, first reported in 1995 by Scherer et al, is a novel and important member of the adipokine family.¹ It is a collagen-like protein that is exclusively synthesised in white adipose tissue and is the gene product of adipose most abundant gene transcript 1 (apM1).

Adiponectin has been postulated to play an important role in the modulation of glucose and lipid metabolism in insulin-sensitive tissues in both humans and animals. Various studies have reported a protective effect of plasma adiponectinagainst type 2 Diabetes Mellitus (T2DM) ^2-6. Adiponectin is also inversely associated with traditional cardiovascular risk factors, such as total and low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and is positively related to high-density lipoprotein cholesterol (HDL-C).⁷ Recent studies suggest that it may have anti-atherogenic and anti-inflammatory properties .^8-10 A few researchers who studied the combined effects of these findings reported inverse correlation between plasma adiponectin and risk of coronary heart disease.^11-15

Recent epidemiological studies have shown that association of adiponectin with insulin resistance and cardiovascular risk factors vary with ethnicity. Mente et al studied the ethnic variations in adiponectin concentrations and insulin resistance and found that South Asians and aboriginal people display a greater increase in insulin resistance with decreasing levels of adiponectin compared to Chinese and Europeans .¹⁶ However, a similar study involving Asian Indian teenagers showed that adiponectin did not correlate directly with measures of insulin sensitivity, overweight, and other cardio-metabolic variables .¹⁷ Similar studies in adults are not available.

The present study was done to assess the association between plasma adiponectin levels and coronary event in patients with diabetes. Also the relation between plasma adiponectin level and various cardiovascular risk factors were studied in patients with diabetes with and without acute coronary event.

Subjects and Methods:

The prospective study was conducted at a tertiary care centre in Bangalore, India from January 2008 to December 2009. The study was approved by the institution ethics committee. Three groups of patients, age and sex matched, were included in the study. The first group included 30consecutive T2DM patients admitted with a diagnosis of myocardial infarction (MI) at the study centre. While the second consisted of patients with T2DM without MI, the third group were patients without diabetes without any history of acute coronary event. MI was diagnosed as per World Health Organization’s criteria.¹⁸ Patients aged less than 18 years were not included in the study. Patients with diabetes with chronic kidney disease or receiving Thiazolidinediones were also excluded from the study as it would alter plasma adiponectin levels.

Fasting Blood Glucose (FBG), Post-Prandial Blood Glucose (PPBG), Glycated Hemoglobin (HbA_1C), Fasting Lipid Profile, Baseline Electrocardiogram and Plasma Adiponectin were done for all the study subjects. In addition, Coronary Angiogram was done for patients with diabetes with MI to confirm Coronary Artery Disease (CAD) and treadmill tests were done for patients with diabetes without MI to exclude underlying CAD.

FBG and PPBG, serum total cholesterol and serum triglycerides were estimated using enzymatic kit method (Vital Diagnostics, Mumbai, India); and serum HDL-C (Bayer Diagnostics, Baroda, India) using a semi-auto-analyser.

Plasma Adiponectin levels was estimated using Human Total Adiponectin/Acrp30 Quantikine ELISA Kit (R&D Systems Inc., India). This assay employs the quantitative sandwich enzyme immunoassay technique. A monoclonal antibody specific for the Adiponectin globular domain has been pre-coated onto a microplate. Standards and samples are pipetted into the wells and any Adiponectin present is bound by the immobilised antibody. After washing away any unbound substances, an enzyme-linked monoclonal antibody specific for the Adiponectin globular domain is added to the wells. Following a wash to remove any unbound antibody-enzyme reagent, a substrate solution is added to the wells and colour develops in proportion to the amount of Adiponectin bound in the initial step. The colour development is stopped and the intensity of the colour is measured.

Statistical Analysis

Statistical analyses were performed using Statistical Package for Social Sciences (SPSS) for Windows 16.0 (SPSS Inc., Chicago, USA). The results for each parameter (numbers and percentages) for discrete data and average (mean + standard deviation) for continuous data are presented in tables and figures using Microsoft office 2007 software package.

Two-way Analysis of Variance (ANOVA) was performed for plasma adiponectin in patients with diabetes with MI, patients with diabetes without MI and controls as the grouping factor. Two tailed ‘P’ values less than 0.05 were considered significant. Spearman correlation was performed to analyse the association between plasma adiponectin, BMI, FBG, PPBG, HbA_1C, serum triglycerides, HDL-C and LDL-C.

Results

The following results are expressed as mean± standard deviation. The mean age of the study subjects in the three groups-patients with diabetes with MI, patients with diabetes without MI and Controls- was 58.00±8.77 years, 57.17±9.34 years and 54.20±7.28 years respectively. The descriptive statistics of the various parameters under study is given in table 1.

Patients with diabetes with MI had significantly lower plasma adiponectin levels (6.11±1.82) when compared to patients with diabetes without MI (9.47±1.55) which in turn was lower than normal subjects (17.82±1.30) (P<.001) . Plasma adiponectin was significantly correlated with BMI (r=-.31), FBG (r=-.61), HbA_1C (r=-.63) and triglycerides (r=-.54) (all P<.001). We did not find any significant correlation between plasma adiponectin levels and HDL-C (Table 2).

Table 1: Descriptive statistics of various parameters under study

Table 1: Patients with diabetes with MI had significantly lower plasma adiponectin when compared to patients with diabetes without MI which in turn was lower than in normal subjects

Table 2: Spearman correlation between adiponectin and body mass index, blood lipids, HbA_1C, fasting and post-prandial glucose levels

** Correlation is significant at the 0.01 level (2-tailed); * Correlation is significant at the 0.05 level (2-tailed); (BMI- Body Mass Index, FBG- Fasting Blood Glucose, HDL- High Density Lipoprotein, LDL-Low Density Lipoprotein, HBA1C- Glycated Haemoglobin, TG- Serum Triglycerides); Plasma adiponectin was significantly correlated with BMI, FBG, HbA_1C and triglycerides (all P<.001). The correlation between plasma adiponectin levels and HDL-C was not statistically significant.

Discussion

In the present study, we found decreased plasma adiponectin concentrationsin the patients with diabetes which was further lower in patients with an acute coronary event indicating that it may be a predictor of macroangiopathy. Hotta et al found similar results in their study and proposed that accumulation of adiponectinin atherosclerotic vascular walls may accelerate its half-lifein plasma, resulting in the reduction of the plasma concentrationof adiponectin in subjects with CAD .¹⁹ Ouchi et al studied the molecular basis of link between adiponectin and vascular disease and found that adiponectinmodulates endothelial inflammatory response and that the measurementof plasma adiponectin levels may be helpful in assessment ofCAD risk. ²⁰ Large scale prospective experimental research is needed to clarify these theories.

The relation between plasma adiponectin and the various known metabolic risk factors were on par with the world literature, except for HDL-C. Koenig et al reported an additive effect of HDL-C and adiponectin on CAD risk prediction. ²¹ In their joint analyses, the highest risk for T2DM as well as acute coronary events was observed in men with low adiponectin in combination with low HDL-C levels. In the present study, the mean HDL-C levels were lower in patients with diabetes with MI compared to patients with diabetes without MI. However, we did not find any significant correlation between plasma adiponectin levels and HDL-C in the present study. Similar findings were obtained by Schulze et al indicating that although plasma adiponectin has been established to be correlated with insulin resistance, CAD and metabolic disease, the interrelation between these is far more complex.

The molecular mechanisms by which adiponectin exerts its multiple functions and whether its actions are receptor mediated still remain a mystery. Is the primary activity of adiponectin antiatherosclerotic, or is it principally a modulator of lipid metabolism and regulator of insulin sensitivity, or is it all of the above? The answers to these and other intriguing questions will undoubtedly provide additional insight into the metabolic roles of this new adipocyte hormone.

Conclusion

The present study and the recent evidence suggest that cross-talk between inflammatory signalling pathways and insulin signalling pathways may result in insulin resistance and endothelial dysfunction that synergise to predispose to cardiovascular disorders. Large scale prospective studies are needed to examine the ability of increase in adiponectin levels and insulin sensitivity to improve primary end points including incidence of diabetes and outcomes of cardiovascular events.

Nearly 30% of seniors have chronic musculoskeletal pain. The most common cause of pain in seniors is related to the degenerative changes of the spine and joints⁹. Conventional treatments are often restricted to the management of symptoms. Use of chronic anti-inflammatory medications in seniors may bear serious risks in gastrointestinal and renal systems. Physical therapy has limited value. Epidural steroid injection(s) may provide up to three months of pain relief. However, there are some risks involved. Spine surgery for degenerative spine diseases has a limited success rate. Up to 30% or 40% of patients may continue to have pain after back surgery. Surgical repair of a knee injury and knee replacement surgeries are popular. However, the costs are relatively high. Many senior patients may not be ideal candidates for surgery due to cardiovascular conditions. Furthermore, all these treatments do not address the key cause of spine and joint pain due to degeneration of cells and subsequent tissue damage⁹. Recent development in stem cells therapy (SCT) has provided a new hope for seniors.

Back Pain

The major cause of back pain is the degeneration of the cells in the intervertebral discs. Over the last few years molecular, cell-based therapies and tissue-engineering strategies with SCT for disc regeneration have significantly increased. A recent report showed that injection of mesenchymal stem cells (MSC) into bovine intervertebral discs can increase the expression of extracellular type II collagen and maximize extracellular matrix production⁷. Chun et al ¹injected human adipose-derived stem cells (ADSCs) into 20 mature male New Zealand white rabbits. The proliferation of ADSCs at the L4-5 disc was found at 10 weeks after cell injection. Histologically, the ADSC-injected discs exhibited elevated extracellular matrix secretion and little ossification of damaged cartilage in the nucleus pulposus compared with degenerative control discs.

In addition to the promising results from animal research, preliminary human studies showed mixed results. In 2006, Haufe et al³ reported 10 patients who underwent intradiscal injection of hematopoietic precursor stem cells (HSCs) obtained from their pelvic bone marrow. Of the 10 patients, none achieved any improvement of their discogenic low back pain after one year follow-up. More recently Orozco et al ⁸ reported a study of ten patients with chronic back pain treated with intradiscal injection of autologous expanded bone marrow MSC. Patients were followed for 1 year. Rapid improvements of pain and disability were reported (85% of maximum in 3 months). Although disc height was not recovered, water content was significantly elevated at 12 months. Advantages of intradiscal MSC therapy include simpler and preservation of normal biomechanics without surgery. However, long term survival of the transplanted MSCs in the harsh environment of the discs is still a major challenge. To the date, no double-blind, controlled studies have been published to confirm the clinical efficacy of SCT for the pain due to degenerative disc diseases.

Knee Pain

It is estimated there will be seven-fold increase in knee replacements in the United States between 2005 and 2030. However, SCT may reduce the future need for knee replacement⁵. Autologous MSC and ex vivo expanded skeletal SC all have shown promising results in the treatment of knee pain caused by osteoarthritis (OA).

In an experimental animal meniscus injury model, it has been reported ¹⁰ that transplantation of human meniscus stem/progenitor cells (hMeSPCs) effectively protected articular cartilage, promoted neo-tissue formation with better-defined shape and more matured extracellular matrix and smother surface cartilage, and maintained joint space at 12 weeks postsurgery¹¹. MSC therapy may also reduce animal pain behavior¹⁴.

In human studies, Turajane et al¹³ conducted a case-series study with five patients that failed conservative treatment. It was reported that the combination of intra-articular autologous activated peripheral blood stem cells with growth factor addition/preservation along with hyaluronic acid in conjunction with arthroscopic microdrilling MCS resulted in Quality of Life improvements and succeeded in regenerating articular cartilage in early osteoarthritic knee disease. Skowronski¹² reported 52 patients treated with autologous blood MSC for knee pain due to cartilage lesions. Scores improved across all scales with an average improvement of 23 points in the Knee Injury and Osteoarthritis Outcome Score scale and 35 points in the Lysholm knee scale at one year.

Koh et al⁴ treated eighteen patients with injection of autologous fat pad-derived MSC for knee pain due to OA. Patients were followed for 24 to 26 months after therapy. Western Ontario and McMaster Universities Osteoarthritis Index, Lyholm scores as well as VAS scores all significantly improved. Radiographic study showed the whole-organ MRI score had significantly improved from 60.0 points to 48.3 points at the final follow-up point. Particularly notable was the change in cartilage whole-organ MRI score, which improved from 28.3 points to 21.7 points. More recently, Vangsness et al reported¹⁵a randomized, double-blind, controlled study on adult human MSC delivered via intra-articular injection to the knee following partial medial meniscectomy. A single superolateral knee injection was given to 55 patients within seven to ten days after the meniscectomy. It was found that there was significantly increased meniscal volume determined by quantitative MRI in groups that received SCT. No patients in the control group had significant increase in meniscal volume. Patients with osteoarthritic changes who received MSC experienced a significant reduction in pain compared with those who received the control. This randomized, double-blind, controlled study confirmed that MSC could be a promising treatment for knee pain due to osteoarthritis and meniscus tear.

Challenges for SCT

The advantage of SCT is that stem cells can regenerate healthy and functionally specialized cells and tissues to replace the destroyed or degenerative tissues. Though it is promising, it is still facing a variety of challenges. Firstly, there are many studies reporting the clinical efficacy, most studies are open label. Only few, if any, double-blind, controlled studies have supported the efficacy of SCT for knee pain due to osteoarthritis. To the date, there are no controlled studies confirming the clinical efficacy of SCT for degenerative spine diseases. Thus more clinical studies are needed. Secondly, biological techniques for stem cell transplantation are waiting to be enhanced. For example, the stem cells transplanted into degenerated intervertebral discs will face a harsh environment, which has very high pressure, low nutrition and low oxygen. To enhance the cell survival rate and ensure the transplanted cells differentiating toward chondrocyte-like cells, which can produce proteoglycans and type II collagen, more basic science studies are needed². The third challenge for SCT is iatrogenic cancerogenesis. Embryonic stem cells, including totipotent stem cells (produced from fusion of egg and sperm), and pluripotent stem cells (5-14 day old blastocytes) have a strong potency of cell reproducing and potentially highly teratogenic. Novel strategies such as using transgenic expression of the genetically engineered human recombinant DNases in proliferating and directed differentiation resisting stem cells are being developed to inhibit or prevent the iatrogenic cancerogenesis⁶. Adult SCs (Adipose, peripheral and bone marrow derived SCs) have the ability to differentiate and form a variety of tissues. These adult SCs have been used in researches to treat variety of human diseases. So far no iatrogenic carcinomas have been reported as the results of the treatment. The fourth major issue related to SCT is the legal challenge. Worldwide, different countries have different laws on SC research and use. Even President Barack Obama signed an executive order on March 9, 2009 to lift the restrictions on federally funded human embryonic stem cells (hESC) research, currently only adult stem cells (adipose, peripheral and bone marrow derived stem cells) are allowed to be used in most clinical settings. These cells should be minimally manipulated. Use of hESC from fetus, umbilical cord and amniotic fluid are all limited for research purposes. Researchers and clinicians must be familiar with the laws of their respective countries and states before becoming involved in SC therapy or research.

Conclusion

The treatment of chronic pain conditions is constantly evolving. Recent advancements in SCT for pain due to degenerative diseases in the spine and joints are promising and indicative that SCT will undoubtedly play a major role in the future. However, more studies are needed to enhance the biological techniques, confirm the clinical efficacy, reduce the risk of iatrogenic carcinoma and address the legal issues related to this exciting treatment. It is likely that SCT will be utilized more extensively in the future for replacing diseased tissues as an alternative to open back surgery or joint replacement.

Introduction

The discharge summary is an integral part of continuing patient care. Apart from containing vital information regarding current admission, it also conveys key findings and plans to clinicians who will be taking over the care of the patient. This would mean communicating important information about patients to ensure appropriate and safe follow-up management. Studies involving discharge summaries have looked into role of communication from secondary to primary care and have highlighted the importance of accuracy and quality of information,¹ errors² and general practitioner (GP) preference.³ Systematic reviews have found low availability (12-34%) of discharge summary during first visit post-discharge as well as wide variations in content of discharge summaries thereby directly affecting patient management.^4,5 The timing of discharge summary completion and reaching the follow-up physician is therefore of prime importance wherein this has been also found to influence and reduce the risk of rehospitalisation.⁶ The content necessary for a ‘good’ or ‘high-quality’ discharge summary has been studied via surveys. The inclusion of important data such as diagnosis, discharge drugs, complications, laboratory results and follow-up plans have been considered to be important clinical information by hospital physicians and GPs.⁷

Hospital discharge summaries can be hand-written, dictated or in electronic format. These formats have their benefits and downfalls. Hand-written summaries have been found to be well-accepted by primary care physicians although involve the factor of legibility.⁸ A randomised-controlled trial found no difference between electronic and dictated discharge summaries for primary care physician satisfaction.⁹ Although the use of electronic discharge summaries has significantly improved both the content and timing of discharge summaries reaching follow-up physician or healthcare staff,¹⁰ they have been found to contain higher number of errors in patient progress, additional diagnosis and free-text components.¹¹

This audit examined the timing and content of discharge summaries at The Mount and whether they met local Trust standards. A follow-on audit was conducted to study the impact of recommendations that had been put forward at the end of Cycle 1 of the audit.

Aim and Objectives

Aim

Cycle 1: To study the content, accuracy and timing of discharge summaries at The Mount, Old Age Psychiatry hospital.

Cycle 2: To examine changes in clinical practice following recommendations from Cycle 1 of audit involving content and timing of discharge summaries from The Mount.

Objectives

Cycle 1: To ascertain whether Trust guidelines regarding content of discharge summaries are met and also whether the timeline guidance is being maintained.

Cycle 2: To examine adherence to the Trust guidelines as well as to study the changes brought about by recommendations at the end of Cycle 1.

Criteria/ Standards

Trust guidelines state:

• Discharge summaries must be typed and sent in 5 working days post-discharge from hospital.
• They must include the following information (Box 1):

Method

Audit Sample

Patients admitted and discharged from Ward 3 & 4 of The Mount, between 01.04.2011 to 31.10.2011. A total of 103 patient discharge summaries were therefore analysed in Cycle 1 of the study. For cycle 2, the audit sample comprised of patients admitted and discharged from Ward 3 & 4 of The Mount, between 01.04.2012 to 31.10.2012. A total of 97 patient discharge summaries were therefore analysed in this part of the study.

Data Collection

Data was collected using an anonymous data collection tool (Appendix 1) which was designed according to Trust guidelines. Administrative staff provided the clinical audit leads with list of patients discharged during the study dates. The electronic patient record system of the Trust (PARIS: Patient Record Information System) was used to study the discharge summary letters. Data collection was performed under the supervision of consultant responsible for the audit, between November 2011 and January 2012 for cycle 1 and for cycle 2 data collection was performed between October 2013 and November 2013. Patient confidentiality and anonymity was maintained.

Data Analysis

Qualitative data was gathered, coded and collated on to a Microsoft Excel spread sheet. The data collected was reviewed by the authors to ensure each aspect of data collection tool was filled. The data was analysed by the Clinical Audits Facilitator at the Trust Clinical Audit Support Team and placed into a report format for dissemination.

Results

The number of discharge summaries analysed in Cycle 1 and 2 of this study was 103 and 97 respectively.

Data were collected using the data collection tool (appendix 1). Dates of discharge, dictation and typing were recorded. Date of typing was used as a proxy of date sent to GP since there was no record of this. Seven days were permitted for discharges to be sent (equivalent to 5 working days). Discharge summaries were read and it was recorded if each stipulated heading from the Trust guidelines was present. No comment was made on quality of information; only consideration was whether information was present or absent.

Compliance with each point from the above categories is shown in the following series of tables and comparison is made between the studies in Cycles 1 and 2 (Table 1-4). The statistical significance of the differences found in the two audit cycles was evaluated using chi-square tests.

Table 1: The presence of information mentioned in the Trust guidelines is analysed. The percentage adherence in cycle 1 is compared with findings from cycle 2. Significant increase in inclusion of family history, social history, follow-up arrangements and date of dictation is observed. A healthy increase is also observed in inclusion of premorbid history and progression and treatment during admission. A significant reduction in spelling/typing errors is also seen. The decrease in inclusion of name of key worker, discharge medications, mental health examination and results of investigation amongst others is also noted. GP, general practitioner.

The comparison of findings from Cycle 1 and 2 establish a significant increase in adherence to family history (p<0.001), social history (p<0.001), premorbid history (p=0.036) as well as progress and treatment during hospital stay (p=0.049) components of the discharge summary. There was also a significant increase in inclusion of date of dictation of discharge summaries (p<0.001). Increase in adherence to most of the components of discharge summaries was observed. However, there was significant decrease in inclusion of follow-up arrangements (p=0.007) as well as a decrease in inclusion of name of key-worker assigned to patient (from 64% in cycle 1 to 56% in cycle 2; p=0.0225). A significant decrease in spelling/typing errors in diagnosis or medical jargon was observed (p<0.001).

Timing of Discharge Summaries

Table 2: The time taken between discharge of patient and dictation of letter is analysed. A significant increase is observed in the dictation of letter as per Trust guidelines (within 5 working days).

Table 3: The time taken between dictation of letter and typing of discharge letter is analysed. A significant decrease is observed in the time taken for typing of letter within 5 days of dictation of letter.

Table 4: The time taken between discharge of patient and typing of discharge letter is analysed. A significant increase is observed in the early typing of discharge letter from the date of discharge of patient.

The number of discharge summaries being dictated and typed within 7 days of discharge was significantly increased (p<0.001) and a significant decrease in discharge letters being dictated more than 2 weeks (p=0.004) or 3 weeks (p<0.001) of patient being discharged was observed. The time taken between dictation of letter and it being typed up was also found to have dropped, with 73% being done within 7 days, significant decrease (p<0.001) being observed since the first cycle. Furthermore, a significant increase is observed in early (less than 7 days) typing of discharge letter since patient being discharged (p<0.001).

Discussion:

The discharge summary is a very important means to communicate medical (both physical and psychiatric) and nursing interventions to the GP or community mental health team. This in turn helps in making invaluable decisions to patient care in the community. Hence, it is worth spending time on doing a good discharge letter which includes relevant information. A timely discharge letter can also be very useful in this regard.

At the end of Cycle 1 of the audit, recommendations that were made included (Appendix 2):

• Disseminating information amongst all junior doctors, consultants and administrative staff on each ward to include the above mentioned headings in accordance with Trust guidelines.
• Information was also provided regarding finding out Name of Keyworker in PARIS system.
• A specific note was also placed regarding to spell out medical terminologies that would assist in the typing of discharge summaries by administrative staff.

From the results, it is evident that the content of the discharge summary has largely been maintained. In other words, good practice was maintained and recommendations from previous audit were implemented in most spheres of discharge letters. However, despite the recommendation of finding out name of key-worker from PARIS system, there was a decrease (from 64% in first cycle to 56% in second cycle) in its inclusion (p=0.225). Thus, training in usage of information technology system is essential. Providing appropriate instruction and training to junior doctors has been found to be useful in improving the quality of discharge summaries.¹² Therefore, it might be beneficial to include instructions or guidelines for appropriate discharge summaries at local Trust or departmental inductions. This will help junior doctors in ensuring completion of accurate and succinct discharge summaries that will aid in patient management.

There was a reduction in documentation of discharge medication, follow up arrangement, mental state examination and physical health investigation carried out as an in-patient. This certainly needs improving as these are the relevant areas to facilitate smooth transition of care in the community and follow-up arrangement. With regard to the timing of the discharge summary, this was found to have significantly improved from the previous audit cycle. For example, the timing between discharge and dictation (within 7 days) has increased from 30% to 73% and almost all discharge summaries are dictated no later than 3 weeks. The possible reasons for delays in dictation could be ongoing workload, availability of medical staff and of the medical notes, as these are sometimes requested by the Intermediate Community Service (ICS) team. There was a slight drop in the time between dictation and typing (from 84% to 73%), which could possibly due to availability of administrative staff, dictation tapes or medical notes and proof reading by medical staff. Significant increase was observed in inclusion of date of dictation of discharge summaries which will be a useful component for future audits. A significant decrease in spelling/typing errors in diagnosis or medical terminologies was observed. Furthermore, there was significant increase in inclusion of family history, social history, premorbid history as well as information on progress and treatment during hospital in the discharge summary. Therefore, timely audit and feedback can be very useful in improvement of discharge summaries and patient care.

Recommendations & Actions:

1. Raise awareness amongst senior house officers (SHO’s) and other doctors in the Trust regarding recording of pre-morbid history, occupational history, name of keyworker as this was only done in 52%, 62%, 56% cases respectively. This could be done by disseminating findings from this audit amongst SHO’s and other doctors of Trust through hand-outs to wards as well as through local teaching session.
2. Remove number of pages from the list of sub-headings needed in discharge summary as this is dependent on typing and not necessarily possible to estimate while dictating discharge summary. However, it is an important part of discharge summary. Therefore, send information with audit findings to medical secretaries informing the need to keep number of pages in the discharge summary.
3. Consider adding a section on documentation of risk assessment should be included in the discharge summary as well as ‘early relapse signature’ which would enable early intervention in the community to avoid inpatient admission. This could be included in the discharge summary. This would involve liaising with consultants and the responsible person for making/printing discharge summaries for Trust.

Introduction

Binge Eating Disorder (BED) was first defined by Stunkard in 1959¹; he identified peculiar food intake features characterized by a loss of control in a subgroup of obese patients. Various efforts have been made, ever since, to provide a non-sociological approach to individuals with such a behaviour disorder, which has long been considered a variant of Bulimia Nervosa.

Unlike patients affected by Bulimia Nervosa, patients with BED appear to be overweight and mainly obese. Thus, the treatment aims not only at reducing BED and its related psychopathology, but also at assessing the weight gain experienced by these patients to prevent a further worsening of physical health.

Walsh & Devlin² evaluated the use of medication in the treatment of Bulimia Nervosa and BED, underlining the efficacy of antidepressant medication in the treatment of Bulimia Nervosa. The antidepressant efficacy led to consider its use in BED more accurately.

Williamson, Martin & Stewart³ stated that pharmacotherapy was not an effective treatment for Anorexia Nervosa. However, it did prove to be successful in Bulimia Nervosa and BED, although subjects affected with eating disorders apparently respond better to psychotherapy approaches.

Systematic investigations have been conducted on the aetiology of BED. Biological and genetic factors, neurotransmitters and hormones have been involved in the onset of binge eating and play an important role in the regulation of hunger and mood.^{4, 5} However, a definitive aetiological theory has not been developed and tested.³

BED is characterized by a relevant psychological component that in many cases is under-evaluated. Patients with BED have difficulty in interpreting the visceral sensations of hunger and satiety; they take large amounts of food even during regular meals and, moreover, their food contains more fat than protein.^{6, 7}

In fact, Axis I and II disorders (DSM IV-TR) share common features with binge eating.⁸ Axis I psychiatric disorders (including depression, anxiety, body dysmorphic disorder, or chemical addiction) characterize many BED patients, and research has evidenced the presence of panic, loss of control, impulsivity, compulsive behavior, obsessive thoughts about food and social phobia.⁹ Axis II personality disorders (especially borderline personality disorder) are frequently related to patients suffering from eating disorder and comorbidity with Avoidant Personality Disorder and Obsessive-Compulsive Disorder was observed.¹⁰

BED is not associated with a restrained eating control, but probably with an increase of uncontrolled eating and emotional eating.^{11, 12}

Pharmacological agents, compared to placebo, have been used in the treatment of BED. Appolinario, Bacaltuchuk, Sichieri et al¹³ evaluated the efficacy of Sibutramine to reduce the frequency of binge eating, while McElroy, Arnold, Shapira et al¹⁴ focused on Topiramate and evidenced a greater reduction in binge eating frequency but with side effects such as paraesthesia.

Other studies showed the efficacy of Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs) in the treatment of obesity associated with BED^{15, 16, 17, 18} showing that SSRIs and Tricyclic Antidepressants (TCAs) reduced the frequency of BED compared to placebo.¹⁹ To determine which patients are most likely to benefit from medications, and how to sequence the various therapeutic interventions available better, are questions still open to debate.

Moreover, results in many cases appear to be divergent. Ciao, Latner and Durso²⁰ underlined the influences of other factors that may influence treatment efficacy. They observed that many obese individuals who might benefit from weight loss treatment nevertheless do not plan or desire to seek treatment and perceive multiple barriers to treatments.

Pharmacotherapy may enhance weight loss,¹⁹ although other results suggest that pharmacotherapy may be associated with a reduction in binge frequency in obese patients with BED, but it does not lead necessarily to weight reduction.²¹ These medical treatments seem to be effective in reducing binge frequency over the short-term, and the subsequent discontinuation of the medication seems to be associated with a relapse of binge eating. Thus further studies of the role of pharmacotherapy in the treatment of BED need to be carried on.²²

According to Williamson, Martin and Stewart³ the additive effects of psychotherapy, e.g. Cognitive Behavioural Therapy (CBT), and pharmacotherapy have to be investigated. At present it seems that adding pharmacotherapy to psychotherapy does not help to reduce binge frequency compared to psychotherapy alone.

The efficacy of CBT has been substantiated by scientific literature^{23, 24, 25, 26} and Vaidya²⁷ stating that CBT helps patients reduce eating disorder habits by making them aware of the cause of their self-sabotage, while affecting weight indirectly.

Psychotherapy treatment over a one-year period deals with binge symptoms and aims at reducing the possibility of relapse by gathering different techniques for the maintenance of long-term results through the use of specific individual intervention protocols. The main target of the intervention is to facilitate the management of no-control food intake episodes and of impulsivity through the alteration of behaviour, and of cognitive and emotional factors related to eating disorders.

Thus, the main objective of this research was to verify the possible differences between those subjects with BED who underwent psychotherapy combined with pharmacotherapy and those who underwent psychotherapy only. In particular, it aimed at verifying possible differences between the various therapeutic strategies on eating behaviour (restrained eating, uncontrolled eating and emotional eating) and the behavioural and psychopathological features (psychopathic deviate, depression and hypomania).

The main hypothesis was to determine if patients who underwent CBT and pharmacotherapy with bio-equivalent doses of the SSRI Paroxetine or SNRI Venlafaxine obtained a considerable benefit from the pharmacotherapy on impulse regulation, on eating behavior and on personality features compared to those who underwent CBT alone.

The second hypothesis was to verify if Paroxetine and Venlafaxine treatments were equally effective on impulse regulation, eating behavior and on personality characteristics.

Methodology

Participants

A group of 30 subjects with BED were selected. All these subjects applied for support to the Inter-Service-Psychology Clinic for Eating Disorders and they were assisted by a Cognitive Behavioural Therapist. They were all of Italian nationality, aged 22 to 52, with a Body Mass Index (BMI) range of 26 to 35. All participants belonged to a middle class socio-cultural level. They were informed of the objectives of the research and signed a consent form. Those subjects who were diagnosed with binge eating less than two years ago, those aged over 65, or those who were suffering from other debilitating or chronic diseases were preliminarily excluded from this research.

Measures and procedure

Participants were recruited according to the nature of the assessments. More specifically, assessments had to address the effect of psychotherapy and pharmacotherapy in subjects with BED on their impulse regulation, their eating behavior (restrained eating, uncontrolled eating and emotional eating), and their personality features (Psychopathic Deviate, Depression and Hypomania). The 30 subjects selected were randomly assigned to three different treatments. Ten subjects had only CBT, ten subjects underwent psychotherapy with Paroxetine, and ten subjects underwent psychotherapy with Venlafaxine.

Each participant answered questionnaires during the assessment phase and in the post-training phase (after one year of psychotherapy). More specifically:

Binge Eating Scale (BES)²⁸ is a 16-item questionnaire which assesses the presence of binge eating behaviour indicative of an eating disorder. The score ranges from 0 to 46 (non-binging <17; moderate binging = 18-26; severe binging = 27 and higher), which in this research had an adequate internal consistency (a = 0.84).

Eating Disorder Inventory-2 (EDI-2)²⁹ aims at quantifying some psychological and behavioural features. It consists of 64 questions grouped into 11 scales. For each item, the participants are asked to answer by using the following frequency adverbs: "always", "usually", "often", "sometimes", "rarely", and "never". The rating is measured with a score between 0 and 3: the maximum score of 3 corresponds to the intensity of the symptom ("always" or "never" depending on whether the direction of the item is positive or negative), score 2 corresponds to a degree intensity immediately below ("usually" or "rarely"), score 1 to an even lower level of intensity ("often" or "sometimes"), while a score of 0 is assigned to the three "asymptomatic" answers. So, those items with a positive direction are assigned the following scores: always = 3, usually = 2, often = 1, sometimes = 0, rarely = 0, never = 0; items with a negative direction are evaluated in the opposite way: never = 3, rarely = 2, occasionally = 1, and often, usually, always = 0. The sub-scale scores are calculated by simply adding all the scores of items of each specific sub-scale.

This research availed the Impulse Regulation Scale with an adequate internal consistency (a = 0.82). This scale shows the ability to regulate impulsive behaviour, especially binge behaviour.

Three Factor Eating Questionnaire (TFEQ)³⁰ is a self-report questionnaire consisting of 51 items.The questionnaire refers to daily dietary practice and measures three different aspects of eating behaviour: (1) restrained eating (conscious restriction of food intake in order to control body weight or to promote weight loss – cut-off: ≤11; a = 0.79); (2) uncontrolled eating (tendency to eat more than usual due to a loss of control over intake accompanied by subjective feelings of hunger – cut-off: ≤8; a = 0.81): (3) emotional eating (inability to resist emotional cues – cut-off: ≤7; a = 0.83).

Minnesota Multiphasic Personality Inventory-2 (MMPI-2)³¹ consisting of 567 items with dichotomy answers (true/false) is most commonly used by mental health professionals to assess and diagnose mental illness. The MMPI is based on ten clinical scales that are used to indicate different psychotic conditions. In this research the scoring of the three following scales were taken into consideration: (1) Psychopathic Deviate Scale (Pd) (50 items) which measures social deviation, lack of acceptance of authority and amorality. This scale can be thought of as a measure of disobedience. High scorers tend to be more rebellious, while low scorers are more likely to accept authority. An adequate internal consistency was obtained in this research (a = 0.83); (2) Depression Scale (D) (57 items). The highest scores may indicate depression, while moderate scores tend to reveal a general dissatisfaction with one’s own life. A sound internal consistency was obtained through this research (a = 0.81); (3) Hypomania Scale (H), with 46 items, identifies such characteristics of hypomania as elevated mood, accelerated speech, locomotive activity, irritability, flight of ideas, and short periods of depression. In this research the internal consistency was a = 0.79.

Results

The Statistical Package for Social Science (SPSS 10.1) was implemented to verify the hypothesis. The limited number of subjects enabled analysis of data through non-parametric statistics. In order to verify statistical differences between simple comparisons on paired data the Mann-Whitney (U) test³² was applied. In order to verify statistical differences within phases (pre- Vspost-training), Wilcoxon Signed Ranks Tests³³ were calculated separately on paired data.

Table 1 synthesizes the means and standard deviations of eating behaviour and of impulse regulation obtained by the three groups: CBT alone; psychotherapy with Paroxetine (CBT+P); and psychotherapy with Venlafaxine (CBT+V) in pre- and post-treatments.

Table 1 – Minimum and maximum scores, Means and Standard Deviations of eating behaviour and of impulse regulation obtained by three differential groups.

By comparing the total scoring in BES during the pre-treatments phase, no statistical differences between groups were noticed. Subjects who only underwent CBT had the same result than those who had addition of Paroxetine (CBT+P) [U = 64; Z = 0.35; p = 0.75] and Venlafaxine (CBT+V) [U = 59; Z = 0.62; p = 0.55]. There were no initial statistical differences between the two groups that received pharmacotherapy [U = 50; Z = 0.1; p = 0.99].

In the post-treatment phases, the presence of binge eating behaviour appeared to be the same in all groups. Subjects belonging to the CBT group obtained the same results as those belonging to the CBT+P [U = 58; Z = 0.68; p = 0.5] and the CBT+V groups [U = 47; Z = 1.36; p = 0.19]. No statistical differences between medication use were noticed [U = 41; Z = 0.69; p = 0.53].

All groups in post-treatment phases seem to equally benefit from the treatment. Comparing scores obtained by participants in the pre- and post-treatments, statistically significant differences were found in subjects undergoing CBT [Z=3.38, p < 0.001] and those with the addition of Paroxetine [Z = 2.848; p < 0.004] and Venlafaxine [Z = 2.859, p < 0.004].

For this research, Impulse Regulation Scale scores were taken into consideration. In the pre-treatment phase relative to each group, all groups showed the same difficulties to regulate impulsive behaviour. The CBT group showed the same impulse regulation as those belonging to the CBT+P [U = 68; Z = 0.12; p = 0.93] and CBT+V group [U = 64; Z = 0.33; p = 0.75]. No initial statistical differences between pharmacotherapy groups were found [U = 45; Z = 0.39; p = 0.74].

In post-treatment, no statistical differences between groups were observed. The CBT group achieved the same results as the CBT+P [U = 60; Z = 0.56; p = 0.58] and CBT+V group [U = 64; Z = 0.32; p = 0.75]. No statistical differences between the use of Paroxetine and Venlafaxine were found either [U = 39; Z = 0.84; p = 0.44].

All groups seemed to benefit from the treatments. In fact, comparing the scores obtained by participants in the pre- and post-treatments, statistically significant differences were observed in subjects who underwent CBT [Z = 3.38, p < 0.001] as well as in subjects supported by Paroxetine [Z = 2.84; p < 0.005] and Venlafaxine [Z = 2.97, p < 0.003].

Table 2 synthesizes the means and standard deviations of different features of eating behavior (restrained eating,uncontrolled eating andemotional eating)showed by the three groups (CBT, CBT+P, and CBT+V) in pre- and post-treatment.

Table 2 – Minimum and maximum scores, Means and Standard Deviations of different aspects of eating behavior (restrained eating, uncontrolled eating and emotional eating) obtained by three differential groups

In eating behaviour as well, all groups in pre-treatment phases appeared to be equivalent. The CBT group had the same mean result in restrained eating than those subjects who also underwent pharmacotherapy [CBT+P: U = 65; Z = 0.33; p = 0.74; and CBT+ V: U = 53; Z = 1.03; p = 0.55]. In the pre-training no statistical differences between groups with pharmacotherapy were noticed [U = 42; Z = 0.59; p = 0.58].

By analyzing the groups in pre-treatment phases no statistical differences in uncontrolled eating behaviour and emotional eating behaviour were found. In pre-treatment phase, the CBT subjects had the same statistical mean in uncontrolled eating [U = 48; Z = 1.33; p = 0.21] and in emotional eating [U = 48; Z = 1.32; p = 0.21] as those who took Paroxetine. No statistical differences were found when comparing CBT subjects with those that were taking Venlafaxine [uncontrolled eating: U = 48; Z = 1.33; p = 0.21; emotional eating: U = 48; Z = 1.32; p = 0.21]. In the pre-training phase there were no statistical differences between groups with pharmacotherapy [uncontrolled eating: U = 46; Z = 1.44; p = 0.17; emotional eating: U = 51; Z = 1.12; p = 0.28] were found.

All groups showed indistinctively less difficulty on restrained eating habits. In fact, by comparing post-training scores, the participants of CBT obtained the same results as those treated with Paroxetine [U = 61; Z = 0.56; p = 0.62] and Venlafaxine [U = 58; Z = 0.75; p = 0.51]. Therefore CBT alone appeared to be less effective on reducing uncontrolled eating than those with the addition of Paroxetine [U = 30; Z = 2.4; p < 0.02] and Venlafaxine [U = 26; Z = 2.6; p < 0.009]. Participants who underwent only CBT presented with less difficulties on emotional eating control than those with Paroxetine [U = 31; Z = 2.31; p < 0.02], but they achieved the same post-treatment score as those supported by Venlafaxine [U = 52; Z = 1.08; p = 0.31].

Comparing post-treatment outcomes, the effectiveness of Paroxetine and Venlafaxine appeared to be the same on restrained eating behaviour [U = 34; Z = 1.2; p = 0.25], on a better controlled eating behaviour [U = 45; Z = 0.39; p = 0.69] and on a higher emotional eating control behavior [U = 33; Z = 1.29; p = 0.2].

Comparing pre- and post-treatment results helped to observe a significant improvement in all groups. Participants who followed only CBT showed less difficulty to restrained eating behaviour [Z = 2.6; p < 0.009] in post-treatment. The same results were observed in those supported by Venlafaxine [Z = 2.12; p < 0.03], while no statistical differences were detected in a post-treatment phase in those groups supported by Paroxetine [Z = 1.89; p = 0.06].

Moreover it was possible to observe a considerable decrease in uncontrolled eating behaviour in all groups [CBT: Z = 3.49; p < 0.0001; CBT+P: Z = 2.84; p < 0.005; CBT+V: Z = 2.88; p < 0.004]. The same results were observed in the way emotional eating was handled. All groups benefited from treatments [CBT: Z = 3.27; p < 0.001; CBT+P: Z = 2.46; p < 0.01; CBT+V: Z = 2.87; p < 0.004].

Table 3 synthesizes means and standard deviations of Psychopathic Deviate (Pd), Depression (D) and Hypomania scales (H) obtained by the three groups (CBT, CBT+P, and CBT+V) in pre- and post-treatments.

Table 3 – Minimum and maximum scores, Means and Standard Deviations of different aspects of Psychopathic Deviate obtained by three differential groups

As evidence of the homogeneity of the groups, the comparisons revealed no statistically significant differences in the pre-treatment phase. The CBT group subjects and those who received Paroxetine [Pd: U = 58; Z = 0.67; p = 0.51; D: U = 55; Z = 0.85; p = 0.39; H: U = 63; Z = 0.41; p = 0.71] showed similar scores. Likewise, the CBT group subjects and those treated with Venlafaxine [Pd: U = 53; Z = 0.99; p = 0.34; D: U = 58; Z = 0.71; p = 0.51; H: U = 65; Z = 0.26; p = 0.79] showed similar scores. The two groups treated subsequently with pharmacological support showed similar initial scores as well [Pd: U = 44; Z = 0.46; p = 0.68; D: U = 50; Z = 0.1; p = 0.99; H: U = 44; Z = 0.45; p = 0.68].

Comparing the results obtained in the post-treatment phase instead, those participants exposed to CBT alone showed a greater reduction of Pd compared to those who had taken Paroxetine [U = 23; Z = 2.76; p < 0.005] and Venlafaxine [U = 23; Z = 2.77; p < 0.005], whereas no differences were found comparing the scores obtained post-treatment in both groups of subjects with pharmacological treatments [U = 41; Z = 0.65; p = 0.53].

In post-treatment, the CBT group participants showed similar scores when compared to those taking Paroxetine [D: U = 54; Z = 0.91; p= 0.37; H: U = 41; Z = 1.67; p = 0.09] and Venlafaxine [D: U = 44; Z = 1.49; p = 0.14; H: U = 49; Z = 1.2; p = 0.23]. There have been no further significant differences in scores obtained post-treatment by the two pharmacotherapy groups [D: U = 39; Z= 0.84; p = 0.44; H: U = 0.47; Z = 0.23; p = 0.85].

All participants seem to have benefited from the proposed treatment. The CBT group had a significant reduction of Pd [Z = 3.3; p < 0.001], D [Z = 3.37; p < 0.001] and H [Z = 3.19; p < 0.001].

A similar result was found by comparing the pre- and post-treatment scores of the subjects supported by Paroxetine [Pd: Z = 2.7; p < 0.007; D: Z = 2.82; p < 0.005; H: Z = 2.82; p < 0.005].

Even in the group treated with Venlafaxine, a significant reduction of Pd [Z=2.87; p< 0.004], D [Z = 2.84; p < 0.004] and H [Z = 2.81; p < 0.005] was confirmed.

Discussion

The use of pharmacological therapy for overweight patients with BED has been less thoroughly studied. SSRIs (Citalopram, Sertraline, Fluoxetine, and Fluvoxamine) have mainly been used as the active compound in the pharmacological trials of patients with BED in order to improve mood symptoms and weight loss.³⁴ Likewise, in many cases, promising results have been obtained with Venlafaxine in BED.³⁵

Most of the research has focused on specific aspects of binge eating disorder, such as reduction in binge frequency and weight reduction. In general the results are associated with higher discontinuation rates.³⁶

In this research, we did not only focus on the binge eating behaviour and impulse regulation in patients with BED. The main objective of this research was to analyze some aspects of eating behaviour (restrained eating, uncontrolled eating and emotional eating) and, more specifically, different psychotic conditions (psychopathic deviate, depression and hypomania).

The first hypothesis of this research was to verify differences between patients with binge eating disorder that followed CBT either with or without a pharmacotherapy support. The results confirmed that CBT and pharmacotherapy are equally effective in the treatment of BED and equally modified patients’ impulse regulation. Paroxetine and Venlafaxine medications did not enhance the control of binge eating or guarantee management of impulse regulation better than CBT alone.

This research also aimed at evaluating the efficacy of CBT with or without pharmacotherapy on some factors related to eating behaviour, such as the tendency to consciously monitor and reduce the caloric intake (restriction), the tendency to lose control on food intake (uncontrolled eating) and the conscious perception of the sensation of craving for food (emotional eating). The results suggest that CBT offers the same results regarding the reduction of caloric intake (restriction) as pharmacological treatment. It is less efficient in reducing the lack of control in food intake (uncontrolled eating), although it helps to reduce the sensation of craving for food (emotional eating) compared to pharmacotherapy.

In this research the effects of standardized treatments of CBT with or without the use of pharmacotherapy with bio-equivalent doses of Paroxetine and Venlafaxine were analyzed on psychopathic deviation, depression, and hypomania. The results confirmed that CBT showed a greater reduction of psychopathic deviation compared to those groups who underwent pharmacotherapy. Moreover, pharmacotherapy led to a higher reduction of depression and hypomania than CBT alone.

The second hypothesis was to verify if the SSRI Paroxetine and SNRI Venlafaxine were equally effective on impulse regulation, eating behaviour and personality features. The analysis showed that Paroxetine and Venlafaxine were equally effective on binge eating control and impulse regulation, but some differences in reducing dysfunctional eating behavior were found. Venlafaxine, compared to Paroxetine, seems to offer a greater improvement in emotional eating and restriction eating behavior. In fact CBT could be efficient to assess the tendency to reduce caloric intake (restriction) and to reduce the sensation of craving for food (emotional eating) more than Paroxetine alone. In order to reduce the tendency to lose control on food intake (uncontrolled eating) it could be helpful to administer Paroxetine or Venlafaxine.

Limitations

While the clinical groups were equivalent in all the parameters taken into consideration in the pre-treatment phase, the absence of a control group (no treatment) significantly reduced the possibility to accurately verify the conclusion. Due to ethical reasons we were not allowed to select a group of patients without any specific treatment. In order to correct this weakness in the research, it might be helpful to extend the sample and analyze the changes over a longer period of time.

It is relevant to analyze appropriately these aspects through controlled trials in order to test the efficacy and long-term outcome of psychotherapy, pharmacotherapy, and psychotherapy in combination with pharmacotherapy for treating BED.

Conclusion

In conclusion, patients with eating disorders usually suffer from other psychiatric disorders besides their eating disorder. Many results also confirm substantial comorbidity among obesity, BED, mood and anxiety disorders and metabolic syndrome in weight loss seeking populations.³⁷

In such cases, it is important to understand the characteristics of the additional psychiatric disorders and the impact these ones have throughout the treatment.

As underlined by American Dietetic Association (ADA) Reports,³⁸ understanding the complexities of eating disorders, such as influencing factors, comorbid illness, medical and psychological complications, is critical in the effectiveness of the treatment of eating disorders.

Eating disorders are complex medical illnesses since they have psychological, behavioural, and physiological components. Previous researchers underlined the importance to investigate gender differences in binge eating and associated behavioural correlates³⁹ and, in order to prevent eating disorders, it is important to carry out individual treatment even on personality traits if the individual disorders have already occurred.⁴⁰ Of course, a multidisciplinary approach involving a collaborative team of psychological, nutritional, and medical specialists as underlined in this research must be pursued in order to obtain important and at least short-term results.⁴¹

The results of this research confirm the need to analyze BED from an integrative perspective and to suggest treatments based on an interdisciplinary approach. The psychological (CBT) and pharmacological (Venlafaxine and Paroxetine) therapies were both efficient in different ways on the reduction of all the negative variables related to eating disorder. However any treatment could be inadequate in the absence of an accurate diagnosis that takes into consideration biological, genetic, psychological and nutritional components.

The assessment phase still plays an important role in determining which treatment is best for each patient. Accuracy in the medical examination when dealing with medical issues, as well as during the assessment examination and the psychological functioning evaluation is recommended.