No

Case

A 41 year old female patient (ASA II) underwent an incision and drainage of her perianal abscess under a general anaesthetic as an urgent procedure. She was known to have anorexia nervosa and was under medical management for it. She had a BMI of 18.5. She also suffered from eczema and mild asthma. She gave a history of irregular heart rhythm in the past. She had a normal ECG and echocardiogram. She was on fluoxetine, salbutamol inhaler, beclometasone inhaler and ricatriptan. She had normal blood investigations prior to induction.

Her anaesthetic was induced with propofol and fentanyl and was maintained on oxygen/ air/ sevoflurane. She was on spontaneous ventilation through a laryngeal mask. She also received paracetamol and ondansetron intraoperatively. She was haemodynamically stable during the twenty minute procedure, which was done in the lateral position.

The laryngeal mask came out ten minutes after her arrival in recovery. The patient asked for pain relief ten minutes after waking up. IV pethidine 25mg (diluted to 12.5 mg/ml) was given by the recovery nurse who, within five minutes, noted severe redness in the distribution of the vein into which it was injected (Figure 1). The anaesthetist was notified, who then flushed the IV line with normal saline. The redness settled down within 15-20 minutes of the start of the reaction ( Figure 2 to 4). The patient was haemodynamically stable and didn't complain of any local or systemic symptoms.

Discussion

Pethidine has been known to release histamine on systemic administration¹. It can also have interactions with various drug groups like SSRIs and MAO inhibitors to cause serotonin syndrome^2,3  and can present with tachycardia, hypertension, hyperthermia, agitation and even seizures, among other signs and symptoms. Pethidine is equipotent to morphine and codeine in terms of histamine release ⁴.

This case is most likely due to profound histamine release in a patient with atopic tendency. The factors thought to increase the incidence and severity of this reaction are ⁵:

• Old age
• Thin body structure
• Poor peripheral circulation
• Volar > dorsal veins
• Repeated injection into the same superficial vein
• High concentration of solution of injection (>10 mg/ml solution)

The factors that have no influence are:

• Pretreatment with an antihistamine
• History of previous pethidine use
• Using pethidine as a premedication

In the past, diluting pethidine with 0.25% procaine also provided protection against the reaction.

There were no other signs of serotonin excess in this patient and she came to no harm. The presentation was dramatic enough to cause concern but was self-limiting.

Figure 1: Time - 0

Figure 2: Time - 5 min

Figure 3: Time - 10 min

Figure 4: Time - 20 min

Introduction

Metastatic carcinoma to the sinonasal tract is rare. We describe a patient with an aggressive follicular variant of papillary thyroid carcinoma who presented with an unusual metastasis to sphenoid sinus.

Case report

A 44 year old Hispanic woman presented at Queens Hospital Center in June 1988 with airway obstruction and was found to have a 10x12 cm firm mass in the left thyroid lobe, and palpable left supraclavicular node. She had no prior history of radiation, and no family of thyroid cancer. She underwent a total thyroidectomy with a modified radical neck dissection. Pathology revealed a follicular variant of papillary thyroid carcinoma: non-tall cell variant. Six of fifty (6/50) lymph nodes were positive. Post-surgery, patient received Iodine-131 ablation therapy (93 mCi) and was placed on thyroid hormone suppressive therapy. Non-stimulated thyrogen total body scan a week after therapy was negative. Thyrogen was not available at that time.

The patient was non-compliant with thyroxine and thyroid stimulating hormone (TSH) was often elevated (13-80 mlU/ml). However, the serum thyroglobulin remained less than 5.0 ng/ml and antithyroglobulin antibody was negative. A repeat total body scan (with 5 mCi I131) 6 months later and 4 years later with thyroxin withdrawal (TSH 36 mIU/ml and 48 mIU/ml respectively) was negative, and patient was continued on thyroxine suppression therapy.

Five years after initial presentation, the patient developed urinary retention and lower extremity weakness. A myelogram revealed block at T1-T2. Patient underwent laminectomy. Pathology revealed metastatic follicular variant of papillary thyroid carcinoma. Since iodine containing contrast was used during the myelogram, I131 iodine therapy was not given. External radiation of 2000 CGY to C7-T5 was administered.

A total body scan 8 weeks post laminectomy (when 24 hour urine iodine < 100 microgram/litre, and TSH was 38 mIU/ml after thyroid hormone withdrawal) was negative, the thyroglobulin level was 5 ng/ml and negative antithyroglobulin antibody (at that period of time, positron emission tomography (PET) scan was not an available option). For the next 2 years of follow up, the patient was maintained on thyroxin suppression therapy, this time with good compliance (TSH 0.1 mIU/ml, thyroglobulin less than 5 ng/ml and negative antithyroglobulin antibody). She did not show up for follow up lumbar computerised tomography (CT).

Seven years after the initial presentation, she complained of headache and double vision, and a three month history of amenorrhea. The thyroglobulin at this time was elevated (20 ng/ml). Chest X-ray was positive for two nodules in the right lung. Magnetic resonance imaging (MRI) revealed a soft tissue mass in the sphenoid sinus, eroding the basi-sphenoid and extending into the nasopharynx (Fig. 1 ABCD). The mass also eroded the sella floor displacing the pituitary gland upwards (arrows). Bone scan revealed focal abnormalities in the upper thoracic spine, ethmoid bones and base of the skull. At that period of time, PET scan was not an available option. Pituitary function testing revealed TSH 0.1 mIU/ml, free T4 level 1.2 mIU/ml.  AM cortisol 5.3 mcg/dl, prolactin 182 ng/ml, ACTH 12 pg/ml, FSH 11.5 mIU/ml, LH 4.0 mIU/ml, and Estradiol 20 pg/ml.

Figure 1: A-T1 weighted midline sagittal MRI scan without contrast. B-T1 weighted midline sagittal MRI scan with contrast. C-T2 weighted axial MRI scan through the lesion. D-Axial CT scans without (on the left) and with (on the right) contrast. Note: The large destructive and enhancing lesion (*) in the sphenoid sinus associated with destruction of the basisphenoid, clivus and sellar floor. Note the normal pituitary gland (arrow) is displaced upwards out the sellaturcica.

Biopsy of the sphenoid sinus mass confirmed that it was metastatic papillary thyroid cancer, follicular variant. The tumour cell nuclear DNA was diploid and P53 and K167 were negative (Impat, NY). The patient was placed on hydrocortisone replacement and continued on thyroxine suppression therapy. Three months later the patient suffered a cardiorespiratory arrest and expired.

Discussion

Metastasis to the sphenoid sinus is rare from any tumour, and from papillary thyroid cancer it is extremely rare. An extensive world literature review revealed only 4 cases of spread to sphenoid sinus region from papillary thyroid cancer_.^1-4

Renal cell carcinoma is the most common tumour of paranasal sinus metastasis, 41.8%. The average age is 58 years, with slight predominance of males. The most common presentation was epistaxis, 31%. The most common causes of sphenoid metastasis are gastrointestinal and renal tumours⁵_.

Von Eiselsberg et  al. in 1893 described one case of metastasising thyroid carcinoma to sphenoid sinus.⁶ Harmer et al., 1899, reported a case of medullary thyroid carcinoma metastasis to sphenoid/ ethmoid sinus and nose. ⁷ Barrs et al. in 1979 reported a case of metastasis of follicular thyroid carcinoma to sphenoid sinus and sphenoid bone.⁸ Chang et al. in 1983 described a case of metastatic carcinoma of the thyroid to the sphenoid sinus.⁹ Renners et al. in 1992 reported one case of metastasis of follicular thyroid carcinoma to the paranasal sinuses, including the sphenoid sinus. ¹⁰Yamasoba et al. in 1994 reported a case with follicular thyroid carcinoma metastasising to sinonasal tract which also included sphenoid sinus.¹¹ In the same year, Cumberworth et al. reported a case of metastasis of a thyroid follicular carcinoma to the sinonasal cavity which head CT showed sphenoid, ethmoid, frontal and maxillary sinuses. ¹²In 1997, Altman et al. described a case of follicular metastatic thyroid carcinoma to paranasal sinuses which included the sphenoid sinus. ¹³ The reported cases of thyroid cancer metastasis to sphenoid sinus are in table 1. Four cases were papillary thyroid carcinoma (included follicular variant of papillary thyroid carcinoma), six cases were follicular thyroid carcinoma, 1 case was medullary thyroid carcinoma and 1 case was unspecified thyroid carcinoma. 

Table 1: Cases of thyroid metastases to the sphenoid sinus

Pathologic lesions involving the sphenoid sinus include inflammatory disease, mucocele, chordoma, nasopharyngeal carcinoma, plasmacytoma, primary sphenoid sinus carcinoma, adenocystic carcinoma, pituitary adenoma, and giant cell granuloma. Benign disease often presents with a more gradual obstruction and disturbance of vision. This contrasts with the acute and progressive disturbances of vision in all cases reported with malignant lesions of the sphenoid sinus.¹⁴

Our patient presented with complaints of double vision for 6 months and headache. After imaging with MRI and given her previous history of metastatic thyroid cancer, the most likely diagnosis was metastases to the sphenoid sinus from the thyroid cancer, which was confirmed by tissue biopsy. Since this patient had evidence of bone metastasis, it is likely that the tumour first metastasised to the bone and then ruptured into the sphenoid sinus. The tumour appears to have eroded the sellar floor, extending into and displacing the pituitary gland, causing secondary hypoadrenalism.

In our patient, low thyroglobulin proved to be an unreliable marker because it was low when the patient had metastasis of the tumour in the spine. These tumours are more aggressive and today, PET scanning has proved more reliable in following them, a modality that was not available at the time for our patient. The possible explanations for negative total body scans in patients with metastatic differentiated thyroid cancer are a) technical limitations of the scan in detecting the tumour cells, and b) failure of the tumour tissue to trap iodine.

There are several unusual aspects in this patient’s presentation. Firstly, the initial presentation was unusual, since this tumour was very aggressive with rare sites of distant metastases. Perhaps the long periods of hypothyroidism when patient was noncompliant promoted the aggressive nature of this tumour. Secondly, the failure of known tumour markers, i.e. serum thyroglobulin and total body scan to identify these metastases. Thirdly, our patient’s tumour cell nuclear DNA was diploid. Investigations have shown that the DNA ploidy pattern as determined by flow cytometry is an important and independent prognostic variable.^15-17 Fortunately, aggressive follicular variant papillary cancer of thyroid (non-tall cell type) is very uncommon.

Generally, total body scan negative with low stimulated thyroglobulin is an excellent prognostic sign. Our patient demonstrates that we need to remain vigilant for the unusual tumour especially when the initial presentation showed so much bulky disease. The need for additional tumour markers will help to identify aggressive well differentiated thyroid carcinoma cases.

Acknowledgement

Appreciation is extended to Ms. Deborah Goss and Mr. Timothy O’Mara, librarians, in helping with literature search and preparing the manuscript. No other financial sources or funding involved in the formation of manuscript. No potential financial conflicts of interest. 

Introduction

Patella fractures account for 1% of all fractures but there is little in the contemporary literature regarding outcomes.  It is accepted that where fixation is required it needs to be rigid and tension band wiring using cannulated screws or k-wires is the accepted standard.¹ Recognised complications associated with this form of fixation occur in up to 15% of cases² and include; infection, loss of fixation, knee stiffness, post-traumatic osteoarthritis, malunion, nonunion and irritation from hardware.³Thereis nothing in the literature regarding the natural history following fixation.

We report an unusual complication of an osteochondral defect being generated as a direct result of a malunion of a patella fracture previously fixed by a tension band wiring technique.

Case Report

A 35-year old lady presented to our unit after a direct fall on to her left knee with an associated dislocation of her patella that spontaneously reduced on extension, at the time of injury. Three years previously she had sustained a patella fracture that had been treated with tension band wiring. From the time of the original fixation she had experienced mild persistent anterior knee pain, with a reduced range of motion and grinding. She had been discharged from further follow up.

On this presentation, examination revealed that she had a marked knee effusion with a functional extensor mechanism and a range of motion from 0-60 degrees.

The initial radiographs demonstrated that she had broken hardware and an incongruency of the patella suggesting malunion on the articular surface with a residual step (figure 1). In addition, an osteochondral fragment was identified in the patellofemoral joint. Computer tomography was undertaken and confirmed the osteochondral fragment had come from the lateral femoral condyle and a spur like prominence on the articular surface of the patella (figure 2). The mechanism was that this bony spur had been driven into the articular surface of the lateral condyle on dislocation resulting in the osteochondral fragment being generated. 

Intraoperative findings confirmed this and measured the osteochondral fragment as 40x15mm (figure 3). In addition it was found that the lateral longitudinal wire had protruded into the joint causing a vertical linear defect in the articular surface of the trochlea.

The osteochondral defect was reduced and stabilized with interrupted 3/0 PDS sutures achieving a smooth articular surface (figure 4). In addition a patelloplasty and a lateral release were performed to remove the bony prominence and restore patella tracking respectively. At 6-month follow up this patient was progressing well with rehabilitation and the majority of her chronic symptoms had resolved.

Figure 1. Lateral radiograph demonstrating an incongruency of the patella suggesting malunion on the articular surface with a residual step

Figure 2. Computerised Tomography confirming an osteochondral fragment that had come from the lateral femoral condyle. 

Figure 3. Osteochondral fragment from the lateral femoral condyle measuring 40x15mm.

Figure 4. The osteochondral defect stabilized with interrupted 3/0 PDS sutures achieving a smooth articular surface

Discussion

Although patellae account for 1% of fractures their functional outcome remains largely ignored in the literature. This case presents an unreported complication and highlights that symptoms can remain following the initial fixation that are accepted either by the patient or the treating centre and not further investigated.

Osteoarthritis of the knee remains the most common musculoskeletal complaint in general practice but even then only a third of those with symptoms seek medical advice. Therefore the lack of re-referrals following fixation is not an accurate way to assess outcome following patella fractures treated with this mode of fixation.

Patella fractures represent only a small number of fractures and therefore assessment of treatment and outcomes is problematic, particularly as there is no standardised rehabilitation regimen.

We report on this case as it illustrates a complication of patella fracture fixation that has not been previously described or routinely recognised and, additionally, highlights the fundamental importance of a comprehensive standardised post-operative imaging follow-up regimen. It may be that patients are not currently being correctly counselled regarding the longer-term expectations following patella fracture. A study to define the natural history of patella fractures following contemporary management is needed.

Introduction

Diabetic patients with peripheral neuropathy are predisposed to foot injury. In Asian countries, a common culture among patients with peripheral neuropathy is to immerse their feet in hot water baths, with a belief that it will “improve circulation” and hence “cure the numbness”. We hereby report three cases of severe burn injuries of the feet presented to our hospital over a span of six months due to the above belief.

Case Report

The first patient was a 53-year old Malay gentleman with poorly controlled diabetes mellitus for six years, complicated with peripheral neuropathy, diabetic nephropathy and right eye cataract (latest HbA1C 8.1%), treated with oral anti-diabetic agents. He had a habit of using hot footbaths for numbness of both feet. Two weeks prior to presentation, due to increased feeling of numbness, he immersed his right foot into a self-prepared tub of hot water with added salt, followed by application of traditional sea cucumber gel. That evening, he noticed blistering of his right foot. Despite advice for admission, he chose to do the dressing as an outpatient in a local clinic. He presented two weeks later due to a worsening wound. At presentation, 4% full thickness burn of his right foot was noted, complicated by secondary infection (Figure 1). He underwent wound debridement, and subsequent split skin grafting. He had a prolonged hospitalization of five weeks due to secondary pseudomonas wound infection requiring parenteral antibiotics.

Figure 1. Right lower limb upon presentation to our hospital

The second patient was a 26-year old Indian gentleman with type I diabetes mellitus for nine years, complicated with diabetic nephropathy and peripheral neuropathy. His wife usually prepared hot water footbaths for him to improve his feet circulation. He developed 5% full thickness burn when he immersed his right foot into a pail of boiling water, not knowing that his wife had not added cold water into the footbath. He presented himself after two days and was hospitalized for two weeks. He recovered after wound debridement and split skin grafting.

The third patient was a 17-year old Chinese lady with poorly controlled type I diabetes mellitus for eight years, complicated with diabetic nephropathy (latest HbA1C 10.0%). She used hot water steam therapy with an aim to cure her recent onset of left foot drop, but was unaware of the temperature of the water. She developed blisters on her left foot, but only presented herself two weeks later when she developed left foot gas gangrene.  She had a prolonged hospital stay of eight weeks with recurrent hospital acquired infections, including Methicillin-resistant Staphylcoccus aureus (MRSA). Despite multiple wound debridement, she required amputation of her left fifth toe (Figure 2).

Figure 2. Left lower limb post Ray amputation

Discussion

Peripheral neuropathy is a known complication of diabetes mellitus. More than 50% of patients who are over 60 years old have this complication.^{1, 2} Thermal injury to the feet in patients with neuropathy has been reported after walking barefoot on hot surfaces³ and after application of hot water bottles or heating pads during winter months.^{4, 5} The use of thermal footbath as a cause of burn injury is mostly due to patient-misuse or ignorance of correct usage.^{6, 7} In contrast, in Asian countries, a common culture among patients with peripheral neuropathy is to immerse their feet in self-prepared hot water without checking the water temperature,⁸ with a belief that it will “improve circulation” and hence “cure the numbness”. This practice has led to accidental burn injuries as described in our case reports.

There are a few reasons why patients with diabetic peripheral neuropathy end up with such a severe complication after the use of thermal footbath. Firstly, the temperature of the thermal bath may be underestimated. The time to develop full thickness burn reduces exponentially with just minimal increments in water temperature.⁹ Secondly, lack of pain despite the burn can prolong exposure to the heat source. In addition, concomitant peripheral vascular disease and endothelial function can limit vasodilatation to conduct heat away hence further aggravate the thermal insult.

Another important contributing factor of complicated wounds are the delays in seeking treatment as the result of lack of pain despite the burn injury. In a study done by Memmel et al on 1794 patients (of which 130 were diabetics) who presented with burn injuries, the majority of non-diabetic burn patients (63%) presented within 48 hours of injury, but only 40% of diabetic patients sought treatment within that time frame. Significantly more patients with diabetes presented after two weeks compared to those without diabetes. As burn injuries are highly susceptible to secondary infection, any delay in presentation further complicates and prolongs hospital stay.^10,11 Not surprisingly, our two patients who presented two weeks after their burn injury had a prolonged and complicated hospital course compared to our second patient who presented soon after the burn injury. Increased susceptibility to infection and delayed wound healing from poor circulation contribute to prolonged recovery and poorer clinical outcomes in patients with diabetes mellitus, with some needing amputation as noted in our third patient.

As a healthcare provider we play a role in preventing this misfortune. Routine screening for the presence of peripheral neuropathy and vascular disease should be done during clinic visits to identify high-risk patients. Specific education regarding avoidance of thermal footbath and consequences of this highly preventable injury should be incorporated into standard diabetic foot care education. If patients choose to immerse their feet in hot water, temperature of the water should always be measured with a thermometer and immersion time should be limited. If a wound develops, they should present early to hospital for immediate treatment.

Conclusion

Thermal footbath for therapeutic purposes is commonly practiced in Asian culture. Our case reports highlight the serious consequences of this practice in diabetic patients with peripheral neuropathy. More public awareness and patient education is needed to prevent these injuries and to avoid the high cost of prolonged hospital stay and losses to the patient.

Introduction

Organ transplantation is an effective therapy for end-stage organ failure and is widely practiced around the world. According to World Health Organization (WHO), kidney transplants are carried out in 91 countries. Around 66,000 kidney donations, 21,000 liver donations and 6000 heart transplants were performed globally in 2005. ¹ In India the rate of organ donation is only 0.16 per million populations, compared to America's 26 and Spain's 35.² The shortage of organ is virtually a universal problem. Though many efforts were undertaken by the government to motivate the public towards donation of organs, the rate of organ donors has not paralleled the growing waiting list³,⁴, ⁵ and inadequate organ donation in India remains a major limiting factor for transplantation. There are several factors which could facilitate and hinder the general public to donate a organ. Identifying these factors could help in planning effective strategies to combat the problem. Hence the present study was conducted with the aim to explore the general publics perceived barriers and facilitating factors of organ donation.

Materials and methods

The present study was a cross sectional, exploratory survey conducted among the general public of Puducherry U.T, India. 400 eligible subjects who fulfilled the following criteria were included a) Subjects aged 18 and above, and b) who understand either the local language Tamil or English. Subjects with intellectual, psychiatric and emotional disturbances that could affect the reliability of their responses were excluded from the study. The population registry in the primary health centers of the selected community area was used as a sample frame to select subjects randomly. Every eligible subject was explained about the purpose of the study and signed a written consent form. Formal ethical clearance was obtained from the institute ethics committee before actual data collection procedure.

Preparation of the questionnaire

An extensive literature review was carried out to understand the possible barriers and facilitators reported in the past. Reported barrier and facilitating factors in the literature were included in constructing the questionnaire, including specific cultural and religious oriented items specific to Indians. Subject’s intention to donate the organ was assessed using a single dichotomous question (yes or no). For assessing the barriers and facilitators related to organ donation a questionnaire with a total of 18 items (9 items each) was prepared in the form of closed ended question i.e. yes or no. Along with closed ended questions, an open ended question i.e. any other? was also included for obtaining an extended response apart from the framed questions. As knowledge is an important factor which could serve both as a barrier and facilitator for organ donation, 8 items related to knowledge were also included as a part of the questionnaire. Knowledge items of the questionnaire were evaluated by assigning a score of 1 for each correct response with a maximum possible score of 8. Interpretation of the knowledge component was also done by categorizing the knowledge as follows - Below 50% of the total score - Inadequate knowledge, 51 – 75% - Moderately adequate knowledge, above 75% - Adequate knowledge, for ease of understanding. The draft tool was validated for its content by 10 experts from the field of surgery, medicine, nursing, anthropology and psychology for its appropriateness. After appropriate modification the content validity index for the tool was calculated and it was found to be highly valid (0.98). The reliability of the tool was estimated by a test re-test reliability method among 10 subjects with an interval of 2 weeks from the first and second time of administration of the questionnaire. It was found to be highly reliable with reliability coefficient of 0.91. A face to face interview method was used to collect data from each subject. Collected data was analyzed using SPSS for windows version 14 (SPSS Inc., Chicago, Il, USA) with appropriate descriptive and inferential statistics. A probability value of < 0.05 was set as the level of significance

Results

Basic Demographic details

Of the total 400 subjects enrolled the majority were male (56%), between the age group of 31-40 years (48%), and followed Hinduism (68%) at the time of interview. Most of the subjects were literate (70%) with education up to high school and resided in a rural area (53%).

Knowledge regarding organ donation

The mean knowledge score of the subjects regarding organ donation was 4.74 1.45 score which ranged from a minimum score of 1 to a maximum score of 8. Most subjects responded correctly to questions related to organ matching (85.3%) and consent procedure (84.7%). Details of different aspects of knowledge regarding organ donation of the subjects can be found in Table 1. When subjects were asked about the source of information regarding organ donation, 51.3% of the subjects reported that they gained knowledge through television, 23% from health personnel, and 12% from friends and 7% through books and internet (Figure1). Whilecategorizing knowledge scores the majority of the subjects (38.6%) had inadequate knowledge, 50.6% had moderate knowledge and only 10.6% had adequate knowledge regarding organ donation.

Intention to donate organs: Barriers and Facilitators

Of the total 400 subjects interviewed 69.75% of the subjects reported that they wish to donate their organs, whereas the remaining 30.25% reported that they will not donate their organs either during their life or after their death. Subsequently the factors for barriers and facilitators were also analyzed using the pretested questionnaire. The most common barriers perceived by the subjects related to organ donation were as follows, ‘family opposition’ (82.8%), ‘complicated organ donation procedure’ (69%), ‘fear that donation affects their future’ (58.36%), and ‘misuse of organs’ (55.2%). More information about barriers is detailed in Table 2.The most important facilitating factors of organ donation as reported by the subjects were ‘thought of saving someone’s life’ (95.9%), ‘feeling of improved sense of humanity’ (95%), ‘to save the life of a close relative’, ‘thought that their organ live after their death (92.6%) and ‘being a role model for others’ (77.7%). More details of facilitating factor can be seen in Table 3

While associating the subject’s intention to donate organs with demographic variables like age, gender, residence, education, religion, marital status, type of family and knowledge; only educational level had a significant association with the subject’s intention to donate organ. Specifically graduate people are more likely to report intention to donate organ their organs than others (p<0.001).

Figure 1: Distribution of source of information regarding organ donation among the subjects.


Table 1: Item wise distribution of different aspects of knowledge regarding organ donation (n=400)

Table 2: Perceived Barriers towards organ donation (n=121)

Table 3: Perceived Facilitators towards organ donation (n=279)

Discussion

The current study was conducted with the aim to explore the general publics intention towards organ donation and to identify the perceived barriers and facilitators. The present study revealed that 69.7% of the subjects have an intention to donate their organs either during their life or after their death, which is similar to the finding of Chung et al⁶ and Shahbazian H et al⁷. Similar to the previous studies⁸ the current study also confirmed a positive association between public intentions to donate their organ with their educational status. Though many studies in the past reported attitudes⁹,¹⁰ of public towards organ donation, the present study was the first of its kind to analyze specifically the barriers and facilitators of organ donation among the general public, this adds strength to this study. The most common barrier reported in the present study was ‘opposition form family in donating their organs’; these findings were similar to a previous study.⁶ Illegal organ donation and misuse of organ is a major problem in India for the low organ donation rate among public¹¹, this fact was reflected even in the current study as 55.2% of the subjects reported misuse of an organ as barrier to organ donation. The most important facilitating factors of organ donation reported in the present study was ‘thought of saving someone’s life’ (95.9%), ‘feeling of improved sense of humanity’ (95%), ‘to save the life of a close relative’ (92.9%), these finding were similar to the findings of Neelam et al conducted in India¹². The majority of the respondents in this study reported "lack of information" about organ donation and transplantation. These findings are comparable with those reported from previous studies, which all indicate the importance of public education about the importance of organ donation¹³,¹⁴,¹⁵,¹⁶. Our study identified that the principle respondents' source of information about organ donation was the television (TV). The contribution of other sources of information in providing respondents with knowledge about organ donation was minimal. Generally, studies had shown the importance of visual media in increasing the awareness of the public about organ donation. ¹⁷,¹⁸

Conclusion

Better knowledge may ultimately translate into the act of donation. Effective measures should be taken to educate people with relevant information with the involvement of media, doctors and religious scholars.

Introduction

Electroconvulsive therapy (ECT) is an effective treatment for some individuals with severe neuropsychiatric illness. It is widely used to treat certain psychiatricdisorders, particularly major depression.^1,2 ECT involves applying a brief electrical pulse to the scalp after the patients are administered muscle relaxants and general anaesthesia.³ This pulse excites the brain cells causing them to fire in unison and produce a seizure.

In 2003, the National Institute of Clinical Excellence (NICE) issued guidance on the use of ECT. Its use was recommended only to achieve rapid and short-term improvement of severe symptoms after an adequate trial of treatment options has proven ineffective and/or when the condition is considered to be potentially life-threatening in individuals with severe depressive illness, catatonia or a prolonged manic episode.⁴

The mechanism of action of ECT is not fully known. ECT affects multiple central nervous system components, including hormones, neuropeptides, neurotropic factors, and neurotransmitters. The induction of a bilateral generalized seizure is required for both the beneficial and adverse effects of ECT. Certain parameters like seizure duration, electric stimuli, seizure threshold, ECT practice factors and medication can influence its effectiveness. The degree to which electrical stimulation exceeds the seizure threshold, the positioning of electrodes on the head, pulse width, pulse frequency and seizure duration are all known to be important.⁵ This study aims to review the evidence base of these parameters in detail. The seizure duration and electric stimulus are the two critical parameters and are therefore the main focus of this review.

Literature Review

A review of literature regarding ECT was using search engines like MEDLINE, PsycInfo, and OVID using the key words “electroconvulsive therapy,” “seizure parameters,” “seizure duration,” “seizure threshold,” “stimulus dosing” and “effectiveness.”

Parameters Associated with Effectiveness of ECT

Relationship between Seizure Duration and Effectiveness of ECT

Very little is documented on clinical studies that correlate ECT effectiveness and seizure duration. There is evidence that supports the direct relationship of seizure duration and the effectiveness of ECT. It was thought that measuring the seizure duration and the knowledge of measuring such parameters can help explain its therapeutic effect.⁶ There has been research which suggests that motor seizures of less than 15 seconds in duration do not exhibit tonic-clonic phases and are ineffective in treatment.⁷ Some of the studies in past years found a direct relationship between total seizure duration during a course of treatment and patient response to ECT.⁸

A retrospective study on ward patients found that a positive clinical outcome from depressive symptoms has a direct relationship with accumulative seizure time in the course of therapy.⁸ However, the study was neither randomized nor controlled. Stimulus intensity, diagnosis, and concurrent medication parameters were not properly considered. Another study that supports the correlation found that 88% of patients with cumulative seizure time of 300 seconds and over had a favourable response. The data was retrospectively and prospectively collected in a university hospital. It was mentioned that data gathering was very difficult specifically with regard to the variable number of patients’ ECT sessions; the confounding effect of medication and the treatment of different patients using unilateral or bilateral.⁹

However other studies challenge these statements. A prospective study of a sample of depressed patients undergoing ECT, the seizure duration did not correlate with Hamilton Depression Rating Scale (HAM-D) scores after treatment. However, it was found that significant nonverbal memory loss of patients was correlated with seizure duration.¹⁰ The seizure duration does not directly influence the frequency of ECT, longer seizures do not equate to fewer ECT treatments. Studies using HAM-D scores do not support the idea that seizure duration is a variable correlated to efficacy.¹¹ Short seizures during ECT for few patients are the result of a medical condition or drug treatment interference. On the other hand, patients who have been subjected to ECT treatment encounter shortened seizures.¹²

There are studies which show that the length of the cerebral seizure activity or the tonic–clonic convulsion is not related to clinical effectiveness.^6,13 However, the treating psychiatrist should question whether, or not, generalised cerebral seizure activity had occurred if, at the first treatment, the convulsion lasted less than 15 seconds or the EEG recording showed seizure activity lasting less than 25 seconds.¹⁴ Such brief seizure activity might be the result of a focal or partial seizure, and therefore be of questionable therapeutic efficacy. It has been noted that there are patients who recover with ECT and yet display only short tonic–clonic convulsions. This may be more likely in elderly patients.

Most recent evidence mentions that the quality of cerebral seizure activity and the quality of the desired activity cannot simply be related to its length in time alone. It is recommended that the convulsion be timed from the end of electrical stimulation to the end of generalised, that is, bilateral, clonic activity. EEG monitoring can also be done but one needs to have good experience using this technique and sometimes artefacts can cause misinterpretation of the results.¹⁵

Relationship between Electric Stimulus and Effectiveness of ECT

ECT is administered by a constant-current, brief-pulse ECT machine that is able to deliver a wide range of electrical dose, that is, 25–50 mC up to 750–800 mC. It is recommended that new machines deliver a range of dose from 25 to 1000 mC.¹⁵ One of the important parameters in predicting clinical response is the degree to which the electrical stimulus exceeds the seizure threshold.¹⁶ The maintenance of adequate seizure duration on patients is a complicated issue. Elderly patients are also more susceptible to cognitive side effects than younger patients.¹⁷ Patients regularly treated with ECT have records of shorten seizure duration over time, and clinicians need to increase stimulus to maintain duration, which in the long run can lead to complications.¹⁸

Electroencephalography (EEG) Findings

Voltage Suppression Studies. Postical voltage suppression refers to the decrease in resting EEG voltage after seizure activity as compared with baseline. Proper excitation of seizures invoke voltage-suppressing neural mechanisms intended to terminate and further seizure activity. This suppression is considered as a lower baseline on the EEG post ictus.¹⁹ According to studies, the degree of suppression correlates with seizure generalization, therapeutic adequacy, and bilateral stimulation.²⁰

EEG Waveform Features. Greater ictal EEG amplitude, intensity, and symmetry obtained with bilateral ECT are not common with longer seizures, but they are related to antidepressant outcome.²¹ Studies found that the immediate post stimulus and mid ictal EEG amplitudes correlated with seizure therapeutic adequacy in depression. The symmetry of waveforms at the midpoint on the EEG tracing was also predictive.²⁰ It was also proven that seizure duration had no impact as an EEG measure of treatment adequacy.²¹

Seizure Charge. The calculated product of EEG voltage, seizure uniformity throughout the brain, and seizure duration was hypothesized to be a measure of treatment intensity and efficacy.²¹ The variables included in total seizure charge are not physiologically independent of one another, which means longer seizure duration will not guarantee better results.

Low-dose bilateralelectroconvulsive therapy has a powerful antidepressant effectbut low-dose right unilateral therapy is ineffective.²² Evidence shows that the efficacy of rightunilateral electroconvulsive therapy depends on the electricaldose.^23,24 There is some research showing that forboth unilateral and bilateral ECT, a higherelectrical dose leads to a more rapid clinical response.^7,17,23

Seizure Threshold and Electroconvulsive Therapy

The knowledge of the seizure threshold is a guide to the selection of the electrical stimulus dose for ECT. In theory, the seizure threshold is the lowest dose of electrical charge for each particular patient that is required to induce seizure.²⁵ In clinical applications the seizure threshold depends on individual patient’s characteristics, treatment history, and other stimulus factors.²⁶

The therapeutic effectiveness of ECT is partly dependent on the degree that the stimulus intensity exceeds the seizure threshold.^27,28 This statement is true on unilateral non-dominant electrode placement (UL) and on relative stimulus intensity. On bilateral (BL) ECT, the therapeutic response frequency is dependent on higher relative stimulus intensity,²⁸ whereas barely suprathreshold UL ECT has significantly reduced antidepressant potency in contrast to moderately suprathreshold UL ECT (150% above threshold).⁶ The clinical use of this can be applied after determining the seizure threshold at the first treatment.^22,29 The desired relative stimulus intensity to be maintained during treatments is confounded by variable increase in seizure thresholds during treatment.²⁸ This rise in the seizure threshold lessens the degree to which a fixed stimulus dosage exceeds the seizure threshold which can result in possible diminished treatment therapeutic potency.

The seizure threshold can be higher in the elderly population and this may increase the difficulty of eliciting effective seizures.^29,30,31 The choice of anaesthetic agent and other age related factors can also affect the seizure threshold. Propofol can reduce the seizure duration and has a possible effect on the seizure threshold.³² The seizure threshold may sometimes rise during the course of therapy. The dose would usually rise pari passu with a rise in the seizure threshold to maintain the dosing strategy. The seizure threshold can increase about 80% in bilateral ECT and 40% in unilateral ECT over a course of treatment.⁶ Some studies found increases of only 25–40% for bilateral ECT.³³

ECT Practice Factors and Seizure Duration

As discussed earlier, the success of ECT treatment can be related to the degree to which the electrical stimulus exceeds seizure threshold and not the absolute dose that determines clinical outcome, especially in unilateral patients.⁶ Right unilateral (RUL) treatment at variable dosage can produce seizures of equal duration to bilateral treatment. With low levels electrical stimulation, RUL patients showed only 17% improvement inHAM-D scores compared to 70% in the BL group, despite the same mean seizure duration.²²

Positioning electrodes over the non-dominant hemisphere causes lesssevere cognitive side effects than bilateral placement.^11,24 In spite of extensive research however, the relative efficacy of right unilateraland bilateral electroconvulsive therapy is controversial.^2,34,35 There are studies which have found superior efficacy with bilateral therapy,^22,36,37 and then there are other studies which have reported equivalent efficacy.^38,39 Because ofthis uncertainty, the American Psychiatric Association TaskForce on Electroconvulsive Therapy recommended thatelectrode placement be determined on a case-by-case basis.²

Multiple ECT stimuli (MECT) is given to patients to achieve longer cumulative seizure durations. The clinical improvement in depression correlates to patients’ total seizure time in MECT. But there is no proven study on the benefits of increased seizure time from the increased number of stimuli administered.⁴⁰

Endocrine Measures

Oxytocin. According to studies, the measurement of oxytocin released from posteriorpituitary has a direct relationship with HAM-D measured improvement in depression.⁴¹ The concentration of oxytocin-associated neurophysin (AON) serum was calculated before and after the patient’s treatment of ECT. The increase in AON positively affects HAM-D. This neurophysin response was evident on ECT treatment but does not relate to EEG-measured seizure duration.

Prolactin. The surge of prolactin released during ECT treatment can be an indicator of clinical improvement. Seizure duration is associated with a rise in prolactin.⁴² However, the relationship between the magnitude of prolactin release and benefits of ECT is yet to be established.²⁴

Cortisol. Although several variables have been studied as a possible predictor for the efficacy of ECT but results regarding hypercortisolism have been inconsistent. There has been a study to evaluate the relation between pre-treatment cortisol levels and the efficacy of ECT in a population of drug-free inpatients with severe major depression. This study suggests that higher levels of post-dexamethasone salivary cortisol at 9 AM are predictive of ECT efficacy.⁴³

Elevated glucocorticoids may increase the vulnerability of the brain to the adverse effects of repeated seizures.This hypothesis was tested in a study and it was found that, ECT treatments delivered over 2 weeks resulted in a significant improvement in mood and a decline in most measures of cognitive performance. Elevated basal cortisol was associated with a greater decline in performance of executive function, visuospatial processing speed, and verbal memory. It was concluded that elevated cortisol predicts a greater degree of ECT-induced cognitive impairment. ⁴⁴

Medication

Concurrent medication. Concurrent therapy can be considered under two headings: general medication and psychotropic medication. Both can affect seizure threshold. Anticonvulsants, hypnotics and membrane stabilisers tend to raise the seizure threshold, while preparations containing theophyllines can have the opposite effect. Concurrent psychotropic medication can have a significant effect upon ECT. Benzodiazepines are anticonvulsant and should be avoided if possible, but it is important to remember that there are risks associated with their sudden withdrawal. Some authorities have suggested short-term reversal with flumazenil if their presence is considered to be a limiting factor in the success of ECT, but experience is limited.^45,46 Tricyclics tend to be proconvulsant, but there is little evidence of any detrimental effect on ECT. Selective serotonin reuptake inhibitors (SSRIs) tend to reduce seizure threshold and may be associated with prolonged seizures. Monoamine oxidase inhibitors increase seizure threshold and it is essential that the anaesthetist is aware that the patient is taking this class of medication or has done so within the previous 2 weeks. Lithium reduces seizure threshold and serum levels should be checked regularly and kept within a moderate range (0.4–1 mmol/l). Selective inhibitors of the reuptake of noradrenaline in common with SSRIs, can reduce seizure threshold and also cause hypertension. Neuroleptics tend to be proconvulsant at low dosage but increase seizure thresholds at higher dosage.

In a retrospective study of 455 patients involving 5482 treatments differences in tolerability and clinical effectiveness were found between combination therapy (ECT administered together with neuroleptic medication) and ECT monotherapy.⁴⁷ Seizure duration which was assessed by EEG was significantly longer in patients treated with combination therapy using neuroleptics with lower antipsychotic potency; whereas seizure duration assessed by EEG-monitoring-electromyograph (EMG) was shorter in combination treatments done with atypical substances. In a parallel study, of ECT monotherapy or combination therapy with antidepressants using the same patient group, seizure duration was unaffected by most antidepressants but SSRIs lengthened seizure activity.⁴⁸ In addition this study found that therapeutic effectiveness was significantly enhanced in the patients receiving tricyclic antidepressants, the tetracyclic antidepressant mirtazapine or SSRIs.

There may also be a role for antidepressants in the prevention of relapse following ECT. A small double-blind placebo controlled study of the tricyclic antidepressant imipramine involving 27 depressive inpatients who had failed on pharmacotherapy prior to ECT showed that imipramine, when compared to placebo, resulted in a significant decrease in the risk of relapse of patients receiving ECT.⁴⁹ This study is in broad agreement with an earlier randomized, double-blind, placebo-controlled trial using another tricyclic antidepressant nortriptyline, or combination therapy of nortriptyline with lithium in the prevention of post-ECT relapse in patients with unipolar major depression.⁵⁰ In 29 patients receiving placebo the relapse rate during the 24 week duration of the trial was 86%; whilst in 27 patients receiving nortriptyline 60% relapsed; and 39% of the 28 patients receiving nortriptyline and lithium combination therapy relapsed during the time of the study.

Other parameters

The effectiveness of the treatment is influenced by many other underlying factors, specifically the conditions and factors relating to individual patients. This would include age, sex, physical health status, co morbidities etc. Thus, one should always consider other factors that might affect the efficacy of ECT. Two recent small Japanese studies have suggested that some cardiovascular and EEG parameters may act as markers to predict the therapeutic response of ECT in depression. Postictal systolic heart rate and blood pressure were found to be significant predictors of the therapeutic efficacy of ECT in a study of 24 patients with depression;⁵¹ with higher systolic heart rate and blood pressure being associated with more effective ECT.

Discussion

ECT is widely used to treat certain psychiatricdisorders, particularly major depression. Although ECT has been extensively used there is little published information on the effect of seizure parameters and the effectiveness of ECT. There is evidence that supports the direct relationship of seizure duration and the effectiveness of ECT but the latest research suggests that the length in time of the cerebral seizure activity or the tonic–clonic convulsion is not related to clinical effectiveness.^10,11 The effectiveness of ECT is related to the quality of cerebral seizure activity and cannot simply be related to its length in time alone. One of the important parameters in predicting clinical response is the degree to which electrical stimulus exceeds the seizure threshold.

Past research has shown that a generalized seizureof adequate duration is necessary and sufficient for antidepressanteffectsand that the intensity of the electrical stimuluscontributes to decreased cognitive function, the principal sideeffect, but not to effectiveness.⁷ Different types of anaesthetics, or concurrent medications can affect the seizure parameters and its efficacy.^52,53 Research shows that a generalized seizureof adequate duration is necessary and sufficient for antidepressanteffects^1,7 and that the seizures of less than 15 seconds duration are ineffective. There are other studies which mention that seizure duration does not influence the effectiveness of the ECT.^10,11

The Future

Clinicians need to continue to research this difficult area within psychiatry to enhance the evidence base and fill such gaps in this evidence as highlighted by the ECT Handbook.⁵⁴ On-going research is needed into what is a proven treatment of depressive illness and this should include more in depth research into the relationship of the above discussed parameters with its effectiveness.

“If ECT is ever legislated against or falls into disuse, it will not be because it is an ineffective or dangerous treatment, it will be because of a failure to supervise and monitor it correctly”⁵⁵ and such supervision includes future quality research by concerned clinicians. Current NICE guidelines have limited the use of ECT to individuals with severe depressive illness, catatonia or a prolonged or severe manic episode who have been unresponsive to other treatment options.In addition, intervention of ECT should be considered to be short term and NICE does not recommend using it as maintenance therapy.⁵⁶ As research into ECT develops, the consequences may be an even more targeted approach to the use of ECT as therapy.

Introduction

Bortezomib is a reversible proteasome inhibitor, currently approved by US FDA for use in multiple myeloma and mantle cell lymphoma. It has been shown to cause new onset and exacerbation of underlying congestive cardiac failure (CHF) in some case reports. Although the exact mechanism of bortezomib induced congestive cardiac failure is unknown, studies have shown dysregulation of ubiquitin proteasome system (UPS) in human cardiac tissues in end stage heart failure^1-3. Furthermore, a study in rats has shown reduced left ventricular contractility after bortezomib administration, which was attributed to reduced ATP synthesis in mitochondria of cardiac myocytes⁴. Our case demonstrates new onset severe reversible left ventricular systolic dysfunction after 4 cycles of bortezomib in a 58 year old female with multiple myeloma. It highlights the importance of monitoring cardiac function in patients receiving bortezomib.

Case Report

A 58 year old female with past medical history of well controlled hypertension presented with severe low back pain, anorexia and unintentional weight loss of around 20 pounds over a period of 3 months in medical clinic. On evaluation of her routine laboratory tests, she was found to have haemoglobin of 6.5 g/dl, haematocrit of 19.9%, white blood cell (WBC) count of 3.9 x 10³/cc, red blood cell (RBC) count of 2.18 x 10⁶/cc and platelet count of 1.52 x 10⁵/cc. Her blood urea nitrogen and creatinine was 10 mg/dl and 0.7 mg/dl respectively and corrected calcium level was 10g/dl. On liver function test, her total protein was 12.4 g/dl and albumin level was 2.8 g/dl. X-ray of lumbosacral spine revealed a compression fracture at the level of T12and L2 vertebra. Bone survey confirmed diffuse osteopenia, severe collapse of the body of T12 and partial collapse of L2 and L3. Due to the presence of severe anaemia and compression fractures, multiple myeloma was suspected. Urine protein electrophoresis showed two monoclonal protein bands with concentration of 46.8% and 4.8% and urine immunofixation showed two intact monoclonal IgA-Kappa immunoglobulin bands. Beta-2 microglobulin level was 5.49. Bone marrow aspiration and biopsy confirmed the diagnosis of multiple myeloma. Patient was staged as IIIA according to Durie-Salmon staging system.

Subsequently, patient was planned to be treated with eight cycles of bortezomib and dexamethasone, with bortezomib being given on day 1, 4, 8 and 11 of each cycle at a dose of 1.3 mg/m² body surface area. Prior to initiation of chemotherapy, she received radiotherapy to spine as well. However, after completing the fourth cycle of bortezomib/dexamethasone, she was admitted to the hospital with generalized weakness, nausea and vomiting. Chest X ray revealed possible right lower lobe infiltrate or effusion along with increased bronchovascular markings and she was treated with antibiotics for suspected community acquired pneumonia. However, an echocardiogram was obtained due to bilateral crackles on physical exam and increased bronchovascular markings on chest X ray, which revealed dilation of left ventricle with left ventricular ejection fraction of 30-35%, diffuse hypo kinesis of left ventricle, mild mitral and tricuspid regurgitation and diastolic dysfunction with abnormal relaxation(Tajik grade I). Left ventricular septal and posterior wall thickness was 0.8 cm. Infiltrative Cardiomyopathy in the setting of multiple myeloma was unlikely due to the absence of bi-atrial enlargement, pericardial effusion and thick bright myocardium on echocardiogram. Cardiology consultation was sought and their impression was new onset left ventricular dysfunction due to bortezomib therapy.

Patient did not receive any further cycles of chemotherapy due to cardiotoxicity and was on optimal medical management for heart failure with lisinopril, carvedilol and isosorbide dinitrate. An echocardiogram was repeated four months after discontinuation of bortezomib, which revealed normal left ventricular contractility with global left ventricular ejection fraction of 55% and trace mitral regurgitation.

Currently, at 2 year follow up, her echocardiogram shows global left ventricular ejection fraction of 65%, trace mitral and tricuspid regurgitation and diastolic dysfunction with abnormal relaxation(Tajik grade I).

Discussion and Review of Literature

Botezomib is a novel proteasome inhibitor which acts by inducing bcl-2 phosphorylation and cleavage, resulting in G2-M cell cycle phase arrest and apoptosis⁵. US Food and Drug Administration (FDA) have approved bortezomib for use in multiple myeloma and mantle cell lymphoma. The common adverse effects of bortezomib observed in clinical trials and post marketing surveillance include thrombocytopenia, neutropenia, hypotension, asthenia, peripheral neuropathy and nausea. US package insert for bortezomib states that acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction and it is recommended to closely monitor patients with risk factor for, or existing heart disease.

The role of ubiquitin proteasome system (UPS) in heart failure has been studied extensively in recent years. Two studies by Hein et al and Weekes et al in 2003 have shown presence of increased amount of ubiquitinated proteins and substrates in cardiac tissues of heart failure patients, indicating reduced activity of UPS in end stage heart failure^1-3. Another study has shown impaired proteasome activity in hypertrophic and dilated cardiomyopathy likely secondary to post translational modification of proteasome⁶.However, in early stage heart failure, there is increased activity of UPS, resulting in remodelling and high cardiac output². Bortezomib, by inhibiting UPS, would lead to accumulation of ubiquitinated proteins in cardiac myocytes, similar to that seen in end stage heart failure. A study in rats exposed to bortezomib alone showed development of left ventricular systolic dysfunction by echocardiography and reduced synthesis of ATP was observed in the mitochondria of cardiac myocytes⁴. However, the exact mechanism of bortezomib induced systolic dysfunction in humans is not clear.

There have been a few reported cases of bortezomib induced congestive cardiac failure in literature (Table 1). The amount of bortezomib administered before development of symptoms of heart failure was 20.8 mg/m² in four patients, 3 mg/m² in one patient and 10.4mg/m² in one patient. Three of them have received prior anthracycline based chemotherapy. Complete reversibility of heart failure after discontinuation of bortezomib was documented only in two cases by follow up echocardiograms and brain natriuretic peptide levels^{7, 8}. The patient described in our index case had well controlled hypertension and no additional cardiac risk factors at baseline. She developed non-specific symptoms, including weakness, nausea and vomiting after the fourth cycle of chemotherapy and was admitted to the hospital for community acquired pneumonia. However, an echocardiogram was obtained due to pulmonary congestion, which uncovered the diagnosis of left ventricular systolic failure. The two echocardiograms obtained at a follow up of 4 months and 2 years showed gradual improvement in ejection fraction to 55% and 65% respectively from 15% after chemotherapy with bortezomib.

We did a review of major clinical trials of bortezomib in patients with multiple myeloma, Waldenstrom’s macroglobulinemia and plasma cell leukaemia (Table 2) to investigate the incidence of congestive cardiac failure reported after administration of bortezomib. In APEX trial, the incidence of congestive cardiac failure was 2% in both bortezomib and high dose dexamethasone group ¹¹. In a study on melphalan refractory multiple myeloma by Hjorth et al, 3 cases of congestive cardiac failure was reported in bortezomib-dexamethasone group and 2 cases were reported in thalidomide-dexamethasone group¹². Another study evaluating the safety of prolonged therapy with bortezomib by Berenson et al reported 1 case of cardiomegaly and 1 case of pulmonary edema¹³. However, further studies are needed to specifically evaluate the incidence of congestive cardiac failure with bortezomib therapy.

In summary, our case and review highlights the importance of maintaining a high level of suspicion for development of congestive cardiac failure after therapy with bortezomib. Given the widespread use of bortezomib and new generation proteasome inhibitors in multiple myeloma, there might be increased incidence of new onset and exacerbation of underlying congestive cardiac failure in future. Currently, there is no guideline for routine evaluation and monitoring of cardiac function in all patients during the course of bortezomib therapy. Furthermore, it is unclear whether the severity of congestive cardiac failure is proportional to the cumulative dosage of bortezomib administration and also, if there is any correlation between onsets of congestive cardiac failure with the timing of bortezomib therapy. Further studies are required in future to address these issues.

Table 1: Review of cases of bortezomib induced congestive cardiac failure reported so far.

*NK: Not Known; **EF: Ejection Fraction

Table 2: Review of cases of congestive cardiac failure reported in clinical trials with bortezomib in multiple myeloma, Waldenström’s Macroglobulinemia and plasma cell leukaemia.
 

Conclusion

CHF is an infrequent but serious adverse effect of bortezomib. Cardiac function should be closely monitored in patients receiving bortezomib, as case reports have shown that these patients might present with non-specific symptoms like weakness and fatigue. Further studies are required to establish the frequency and mode of monitoring of cardiac function during and after bortezomib therapy.

INTRODUCTION

The US Food and Drug Administration (USFDA) considers the following as biologics: any therapeutic serum, toxin, antitoxin, vaccine, virus, blood, blood component or derivative, allergenic product, analogous product, or derivatives applicable to the prevention, treatment, or cure of injuries or disease of man¹. However, generally, biologics refer to protein molecules therapeutically used in various diseases so as to target specific points in the inflammatory cascade of these disorders ². Hope for an improved tolerability, convenience in usage and lasting remissions, combined with increased knowledge of immune-pathogenesis of various cutaneous diseases has lead to the introduction of biologics as alternative immune-modulating agents in the field of dermatology.

CLASSIFICATION

Biologics are generally divided into three major groups ³:

a) Monoclonal antibodies

b) Fusion antibody proteins

c) Recombinant human cytokines and growth factors

The main groups and the principal agents in each group are summarised in Box 1 and described below.

A) MONOCLONAL ANTIBODIES

Monoclonal antibodies target specific cell-surface receptors. In the early days of biologic therapy, purely murine monoclonal antibodies were used. However, due to the development of antimurine antibodies, which blocked their action, these could be given only for very short periods. The monoclonal antibodies used now have different amounts of murine sequences in the variable region. They may be categorised into three classes:

(a) chimeric antibodies comprising of 30% murine genes fused with human antibodies

(b) humanised antibodies, which have 10% murine sequences, and

(c) human antibodies, which are solely derived from human immunoglobulin genes ⁴.

Principal monoclonal antibodies with therapeutic relevance in Dermatology

The principal monoclonal antibodies known till date are enumerated in Box 1 and described briefly below.

1. Infliximab

Infliximab (trade name Remicade) is a human-mouse monoclonal antibody that binds to and inhibits the activity of TNF-α, and also causes lysis of TNF-α producing cells⁵.

Important uses of Infliximab

Psoriasis: Infliximab is approved for the treatment of psoriatic arthritis and plaque psoriasis by FDA^{6, 7}. Infliximab may also be of value in recalcitrant or unstable disease and in generalised pustular psoriasis. It is given as an IV (intravenous) infusion in doses of 5 or 10 mg/kg, over a period of 2 hours at weeks 0, 2, 6 and may be followed by repeat single infusions at 8-12 week intervals ⁸. In various controlled trials, improvement at 10 weeks has been noted in 87% of patients ^{7, 9}.

Atopic dermatitis: Infliximab has also been evaluated in a study of atopic dermatitis ¹⁰. At 2 weeks, there was significant improvement in all patients. At 10, 14, and 30 weeks, variable response was seen.

Hidradenitis suppurativa: Long-term efficacy has also been evaluated in hidradenitis suppurativa. In one study, some patients had no evidence of recurrence after 2 years, while others relapsed within a mean of 8.5 months¹¹.

2. Adalimumab

Adalimumab (Humira®) is a human IgG1 monoclonal antibody directed against TNF-α. Adalimumab is given in a dose of 40 mg subcutaneously (SC) every other week as self-injection ^{5, 12}.

Important uses of Adalimumab

Psoriasis: Adalimumab rapidly reverses the decrease in epidermal Langerhans cell density in psoriatic plaques ¹³. In a trial, patients with psoriatic arthritis received adalimumab every other week for 24 week¹⁴. It was well-tolerated and helped improve joint and skin manifestations significantly.

Hidradenitis suppurativa: An increasing number of reports in refractory hidradenitis supprativa have shown successful control with adalimumab ^{15, 16, 17}.

3. Basiliximab

Successful treatment for severe psoriasis and generalised pustular psoriasis has been reported with basiliximab, an interleukin-2 receptor (IL-2R; CD25) chimeric monoclonal antibody ^{18, 19}.

4. Daclizumab

Daclizumab is a humanised monoclonal antibody thatbinds to the CD25 subunit of the IL-2 receptor onT-cells, thus blocking T-cell proliferation. It has been tried in recalcitrant psoriasis and HIV-associated psoriatic erythroderma with a mean reduction in PASI of 30% ^{20, 21 22}.

5. Siplizumab

Siplizumab (Medi-507) is a humanisedmonoclonal antibody directed against CD2. It is designed to block stimulationby inhibiting the CD2–LFA-3 interaction. In earlyphase studies in psoriasis, significant response to therapy has been noted²³.

6. Efalizumab

Efalizumab is a recombinant humanised monoclonal IgG1 antibody that binds to CD11a, a subunit of leukocyte function-associated antigen 1 (LFA-1) ²⁴. It destabilises and decreases the trafficking of T-cells into dermal and epidermal tissues.

Important uses of Efalizumab

Psoriasis: Efalizumab was approved by the US FDA in October 2003 for the treatment of psoriasis⁵. It is currently the only biologic agent approved for continuous administration to adult patients²⁴. The licensed dose of efalizumab is 1 mg/kg weekly as a subcutaneous self- administered injection for 12 weeks, following a first conditioning dose of 0.7 mg/kg ²⁴.

Lichen planus: There is one case report of 3 months duration of treatment with efalizumab for lichen planus with resolution of skin lesions and pruritis ²⁵.

7. Rituximab

Rituximab is a monoclonal humanised antibody directed again in the B cell-specific antigen CD20.

Important uses of Rituximab

Lymphoma: It has been used in patients with CD20-positive non-Hodgkin's lymphoma in a dosage of 375 mg/m² for four infusions²⁶.

SLE: In systemic lupus, dose escalation studies revealed no differences with respect to clinical outcome in patients who received either a single infusion of 100 mg/m², a single infusion of 375 mg/m², or four weekly infusions of 375 mg/m^{2 27}.

Blistering diseases: For patients with blistering diseases, most patients receive the lymphoma dosage schedule. However, serious side effects were considerably higher.

There are reports of refractory pemphigus patients who received infusions of rituximab and had rapid resolution of lesions and a long lasting clinical remission ^{28, 29, 30}.

8. Galiximab

Galiximab a humanised monoclonal antibody directedagainst CD80 and blocks its interaction with CD28 on the T cell, for T-cell stimulation ³¹. Clinicaldata for this drug are just beginning to emerge with 40% of patients achieving at least 50% reduction in PASI after receiving4 biweekly doses in a trial^{32, 33}.

9. Ustekinumab

It is a fully human monoclonal antibody targeting IL-12 and IL-23, presently undergoing clinical trials for psoriasis and psoriatic arthropathy^{2, 34}. In placebo-controlled studies, (PHOENIX 1) and (PHOENIX 2) have shown that ustekinumab could control plaque psoriasis with only four injections a year resulting in greater ease of use and more sustained relief ^{35, 36}.

10. Certolizumab pegol

Certolizumab is the recombinant antibody Fab' fragment of a humanised TNF inhibitor monoclonal antibody. A study in chronic plaque psoriasis showed that certolizumab pegol, given subcutaneously every two weeks, over a period of 12 weeks shows significant improvement ³⁷.

11. Golimumab

Golimumab, a fully human monoclonal antibody is at present undergoing Phase III clinical trials in psoriatic arthropathy ³⁸.

12. Orthoclone or OkT4a

It is a humanised antihuman CD4 IgG4 monoclonal antibody preventing the recognition of the MHC-bound antigen by an appropriate T-cell receptor, hence T cells do not get activated ³⁹. Several studies have found orthoclone to be effective in moderate to severe psoriasis ^{40, 41}.

13. ABX-IL8

ABX-IL8 is a fully human monoclonalantibody designed to bind free IL-8, a key chemokine in psoriasis and deactivate it in theskin^{42, 43}. In early trials, the drug has demonstrated good clinical responsein psoriasis ^{44, 45}.

14. Omalizumab

Omalizumab is a recombinant, humanised, monoclonal antibody against immunoglobulin IgE. This agent acts as a neutralising antibody by binding IgE at the same site on IgE as its high-affinity receptor, FcεR _I, thus inhibiting the biological effects before the generation of allergic symptoms ⁴⁶. There are reports of the efficacy of omalizumab in chronic urticaria ⁴⁷, cold urticaria ⁴⁸ and atopic dermatitis ⁴⁹.

15. Mepolizumab

Mepolizumab is a humanised monoclonal IgG antibody to the IL-5 molecule, which is essential for eosinophil growth and differentiation. Two weekly infusions showed significant clinical improvement in atopic dermatitisand clinical trials are underway for hyper-eosinophillic disorders ^{50, 51}.

16. SMART Anti–IFN-γ

SMART anti–IFN- γ,a humanised monoclonal antibody, binds and inactivates IFN- γ, an important Th1 cytokinein psoriasis. Early phase studies are being performed at this time ⁵².

B) FUSION ANTIBODY PROTEINS

Fusion proteins, also known as chimeric proteins, are proteins which are created by the fusion of the receptor domain of a human protein with the constant region of human IgG. The resultant fusion protein binds specifically to a ligand or co-receptor ⁵³. The most commonly used fusion proteins in dermatology are briefly described below and enumerated in Box 1.

1. Alefacept

Alefacept is a bivalent recombinant fusion protein composed of the first extracellular domain lymphocyte function antigen 3 (LFA-3), fused to the hinge domain of human IgG1. The LFA-3 portion of alefacept binds to CD2 receptors on T-cells, thereby blocking their natural interaction with LFA-3 on antigen presenting cells (APCs). The IgG1 portion of alefacept binds to FcγR receptor on natural killer cells to induce T-cell apoptosis ⁵⁴.

Important uses of Alefacept

Psoriasis: The US FDA approved alefacept in January 2003 for treatment in adult patients with moderate to severe chronic plaque psoriasis. It is given by intramuscular or intravenous route with a dose of 10-15 mg IM weekly or 7.5 mg IV weekly and a 12 week course is recommended ^{5, 54}. Two 12-week courses showed a75% or greater reduction in the PASI ⁵⁵.

Alopecia areata: Case reports have shown that alefacept may be effective in the treatmentof AA^{56, 57}.

Pyoderma gangrenosum: Alefacept has been used for pyoderma gangrenosum and improvement was shown in 25% of these patients ⁵⁸.

Other Indications

Some of the off-label conditions where alefacept has been used with success are graft-versus-host disease (GVHD), lichen planus, alopecia areata, atopic dermatitis, mycosis fungoides,alopecia universalis, erosive lichen planus,Hailey-Hailey diseaseand hand dermatitis ^{58, 59, 60, 61, 62, 63}.

2. Denileukin diftitox

Denileukin diftitox is a novel recombinant fusion protein consisting of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptors. It was tried in patients with recalcitrant psoriasis and the rate of improvement for treated patients was found to be significant ⁶⁴.

3. Abatacept (Ctla4ig)

It is a fusion protein composed of the extracellular domain of CTLA4 and the Fc region of IgG4. It interferes with T-cell activation by competitively binding the B7.1 and B7.2 molecules on the surface of APC ⁶⁵. In a study, patients with stable psoriasis vulgaris showed good improvement with IV infusion of abatacept ³³. A second generation CTLA4Ig, Belatacept, is currently under Phase II clinical trial for allograft diseases ⁶⁶.

4. Etanercept

Etanercept is a recombinant fully human dimeric fusion protein comprising of the human TNF-α p75 receptor and the Fc portion of human IgG1 molecule. It functions as a TNF inhibitor, thereby preventing interaction with its cell surface receptors on target cells and blocking its pro-inflammatory effects.

Important uses of Etanercept

Psoriasis: Etanercept (Enbrel®) is FDA approved for use as subcutaneous monotherapy in psoriasis. Several clinical trials have shown that it is effective^{67, 68, 69, 70}. The adult dose is 50 mg/week, given subcutaneously for three months ⁵. The drug is also indicated for treatment of psoriatic arthritis ^{71, 72}.

Hidradenitis supprivata:There is a study of etanercept in patients with severe hidradenitis with more than 50% score improvement¹².

5. Onercept

Onercept is a recombinant human soluble p55 tumour necrosis factor binding protein under development for the potential treatment of psoriasis and psoriatic arthritis⁷³.
C) RECOMBINANT HUMAN CYTOKINES AND GROWTH FACTORS

Cytokines are non-immunoglobulin proteins and glycoproteins produced by a wide variety of cells in the human body and released in response to any immune stimulus ^{74, 75}. Recombinant cytokines or cytokine antagonists have been used as immunomodulators ⁷⁶. The principal recombinant cytokines used in dermatology, enumerated in Box 1, are described below.

1. Interferons (IFNs)

IFNs, a family of related proteins, are produced by virus-infected leucocytes. They exhibit anti-proliferative, immune-modulatory and anti-neoplastic functions ⁷⁷.

· Interferon α

Recombinant IFNα is given as a subcutaneous or intramuscular injection to treat verruca vulgaris ⁷⁸ , condyloma acuminatum ⁷⁹, cutaneous T cell lymphoma ⁸⁰, Kaposi's sarcoma (AIDS related) ⁸¹, melanoma ⁸², basal cell carcinoma ⁸³, squamous cell carcinoma ⁸⁴, actinic keratosis ⁸⁵, Behçet's disease ⁸⁶, hemangiomas ⁸⁷ and keloids ⁸⁸.

The injections are usually given thrice weekly and the dose (depending on the condition being treated) varies from low-dose therapy for condyloma acuminatum to high-dose therapy for melanoma ^{89, 90}. Of late, pegylated IFNα is being used for convenience, because it has a longer half-life and hence can be given once weekly ⁸⁰.

· Interferon-γ

It is FDA approved for the treatment of chronic granulomatous disease ⁹¹ and has also been used in atopic dermatitis ⁹² and cutaneous T cell lymphoma ⁹⁰.

2. Interleukin 1 receptor antagonist (IL1Ra, Anakinra)

Anakinra is the non-glycosylated form of human IL-1Ra and acts by blocking the functions of the naturally occurring IL-1⁹³. Good results have also been reported in Schnitzler's syndrome⁹⁴, familial cold auto-inflammatory syndrome ⁹⁵ and psoriatic arthropathy⁹⁶. It is given by subcutaneous injection 100 mg once a day.

3. Interleukin 2

Recombinant IL-2 is an antitumour cytokine that has been used in cutaneous T cell lymphoma (CTCL) and metastatic melanoma ⁹⁷. When given intravenously in high doses of 600,000-720,000 IU/kg in melanoma, IL-2 has produced a 15-20% overall response, with complete cure in 4-6% ⁹⁸.

4. Interleukin 4 (rhIL-4)

In a dose-escalation study (0.5 to 5mg/kg given by subcutaneous injection thrice a week), IL-4 has been shown to cause improvement in psoriasis by inducing Th2 differentiation in human CD4 ⁺ T cells ⁹⁹.

5. Interleukin 11 (rhIL-11, Oprelvekin)

It has also shown reasonably good results in the treatment of psoriasis at doses of 2.5 or 5mg/ kg, by subcutaneous injection ¹⁰⁰.

6. Granulocyte macrophage colony stimulating factor (GM-CSF)

GM-CSF acts by stimulating stem cells to produce granulocytes, monocytes and macrophages ¹⁰¹. Recombinant human GM-CSF has been used to promote wound healing in ulcerated skin for example leg ulcers ^{102, 103}, and for the treatment of melanoma ¹⁰⁴ and Sezary syndrome ¹⁰⁵.

7. Platelet derived growth factor (PDGF)

PDGF is a dimeric glycoprotein which regulates and promotes granulation tissue formation, re-epithelialisation and wound angiogenesis ¹⁰⁶. Recombinant PDGF-BB topical gel (100ìg/g), applied once daily, has been approved by FDA for the treatment of diabetic foot ulcers ^{107, 108}.

8. Recombinant Human IL-10

Recombinant Human IL-10 (Tenovil)can be given in subcutaneousinjections. Early phase clinical trials have shown thatrecombinant human IL-10 three times a week improved psoriasis ^{109, 110}.

SIDE EFFECTS OF BIOLOGICS ^{5, 111, 112, 113}

Some of the adverse effects of biologics are described below:

• Allergic reaction and antibody formation: Mostly seen with TNF-α blockers.
• Mild transient injection site reactions: Comprising of erythema, oedema and bruising, noted with etanercept in 10-20% of cases in the first month of therapy. Antibodies to etanercept may develop in 6% of patients.
• Infusion reaction: Occurs during or within 1-2 hours of treatment and may affect up to 20% of all the patients treated with infliximab, rarely anaphylactic shock may occur.
• Acute flu-like symptoms: Headache, chills, fever, nausea and myalgia may occur within 48 hours after administration of the first two doses of efalizumab and Interferon α.
• Infections: Reactivation of tuberculosis may occur on treatment with anti-TNF-α agents and sepsis secondary to Listeria monocytogenes and Histoplasma capsulatum have been reported ¹¹³.
• Malignancy: Patients previously treated with PUVA represent an at-risk group.
• Demyelinating disease: Worsening of multiple sclerosis and demyelination reported with infliximab.
• Thrombocytopenia: Occurs with efalizumab and warrants discontinuation of therapy.
• Autoimmune haemolytic anemia: Occurs 4-6 months after the start of treatment with efalizumab.
• Congestive cardiac failure: Worsening of congestive cardiac failure with TNF-α blockers is reported to occur.
• Antinuclear antibodies and lupus-like syndrome: May develop during therapy with anti-TNF-α agents, but not associated with symptoms and signs of lupus in the majority.
• Hepatitis: Reported following infliximab therapy, occurring from 2 weeks to more than a year after initiation of treatment. Treatment should be stopped in the event of jaundice and/ or marked elevations (>5 times the upper limit of normal) in liver enzymes.

PATIENT SCREENING FOR BIOLOGIC THERAPY ^{113, 114}

All patients to be put on biologics should undergo a thorough evaluation including detailed clinical history, physical examination and relevant investigations with particular reference to known toxicity profile of the agent being considered. The investigations generally advised are¹¹³: full blood count, liver and renal function tests, screening for hepatitis and HIV infection, anti-nuclear antibodies, anti-ds DNA, urine analysis, chest X-ray and Tuberculin skin testing.

For efalizumab, haemogram (including platelet count) is recommended monthly for the first 3 months and then every 3 months. For TNF blockers, it is done at 3 months initially and repeated every 6 months.

Liver and renal function tests, serum electrolytes and urine analysis are done at 3 months initially and then every 6 months.

EXCLUSION CRITERIA/ CONTRAINDICATIONS

There are various contraindications for use of biologics, warranting their exclusion and precautions are to be exercised because of their immune-modulator properties. The main exclusion criteria are: active tuberculosis, severe congestive heart failure, patients having >200 treatments of PUVA (because of a risk of developing malignancies with anti- TNF agents), history of demyelinating disease or optic neuritis, hepatitis B and C positivity, HIV positivity, premalignant states, active infections and high risk states such as chronic leg ulcers, persistent or recurrent chest infections and indwelling urinary catheter infections, pregnancy and breast-feeding.

ASSESSMENT OF THE RESPONSE TO BIOLOGICS

Many scoring systems for assessing the severity of various dermatological diseases exist. These scoring systems and other indices can be used for assessment of response to the use of biologics. For example, for evaluation of improvement in psoriasis, PASI (psoriasis area and severity index) and DLQI (dermatology life quality index) are recommended at 3 months initially and then every 6 months ¹¹³. Reduction in baseline PASI score of >75% is the standard used by FDA to assess the efficacy of a new psoriasis agent ¹¹⁵. Similarly in atopic eczemas, improvement is monitored based on the Eczema Area and Severity Index, Pruritus Severity Assessment and DLQI. Reduction of the Eczema Area and Severity Index score by 50% is considered excellent, 30-49% moderate and <29% non-significant.

SUMMARY

To summarise, biologics represent the future of therapeutics, not only in dermatology but also in other fields of medicine. Among the various dermatological disorders where they are used, biologics have been most evaluated in psoriasis ¹¹⁶. However, the possibility of serious infections and the oncogenic potential combined with the high cost of the drugs limit their routine use at the present stage ¹¹⁷. Regular re-evaluation of efficacy and safety is essential if these agents are to be used to the maximum benefit of patients¹¹⁸.

Introduction:

Colorectal cancer (CRC) is the third most common cancer in men and women worldwide (1) and a leading cause of cancer related deaths (2). 5FU synthesized in 1957 by Heidelberger (3) is the mainstay in all current standard regimens for CRC (4). Chemotherapy induced hepatic toxicity in 5FU based regimens can be an acute or delayed outcome (5, 6); whereas steatosis is a hallmark of 5FU induced hepatic toxicity (7). Chemotherapy induced nephrotoxicity (8) is also an area of concern for oncologists. The antimetabolite 5FU is often linked with kidney damage (9). Therapeutic outcomes and toxicity of 5FU differs markedly in different doses, combinations, schedules of administration and routes of administration. Leucovorin (LV) incorporated in 5FU based regimen enhances the cytotoxicity of 5FU. In this study we opt to report abnormalities in hepatic enzymes and renal biomarkers biochemically assessed in the serum after alternate cycles of treatment in CRC patients subjected to 5FU/LV based chemotherapy.

Methods:

The study was designed in the Department of Pharmacology, University of Karachia and conducted in a leading cancer hospital in Pakistan. Following institutional authorisation, informed consent was obtained from patients being admitted during 2008-2011. The inclusion criteria was maintained on the following grounds:

1. Histologically confirmed advanced colorectal carcinoma
2. Adequate blood count before therapy
3. Age 20-80 years
4. ECOG score of < 3
5. Serum bilirubin < 5× normal
6. Serum creatinine < 135µmol/liter
7. Serum transaminases < ×2.5 normal

Twenty three patients (median age 59 years) who underwent surgery were included in the study. All the patients had measureable disease at CT scan, ultrasonography or clinical examination. Patient’s characteristics are shown in Table 1. Seventeen patients were treated with the adjuvant bimonthly regimen of 5FU/LV - high dose Folinic acid (de Gramont Regimen); whereas, six patients were treated with adjuvant monthly regimen of 5FU/LV –low dose Folinic acid(Mayo Clinic Regimen) as follows.

5Fluorouracil/ Leucovorin (de Gramont’s regimen)

5Fluorouracil: 400mg/m² IV followed by 600mg/m² CIV for 22 hours on day 1-2.
Leucovorin: 600 mg/m² IV as 2 hours infusion before 5FU on day 1-2.
Cycle repeated after 2 weeks.

5Fluorouracil/ Leucovorin (Mayo clinic regimen)

5Fluorouracil: 425mg/m² IV on day 1-5.
Leucovorin: 20 mg/m² IV before 5FU on day 1-5.
Cycle repeated after 4-5 weeks.

Premedication with oral phenothiazines, 5HT₃RA and 10-20 mg of dexamethasone was given.

The blood samples were collected before the initiation of the therapy and after each alternate cycle of treatment. The blood was drawn when the patient was rested and comfortable from the antecubital vein under minimal tourniquet pressure. The blood drawn was sampled and collected into vacutainers (BD). The biochemical profile of the pretreatment and subsequent treatment was comparatively assessed. SGOT, SGPT, bilirubin and alkaline phosphatase levels were measured after each cycle of treatment or on the clinical presentation of any hepatic adverse effect notified by the physician or oncologist and the levels were compared to the pretreatment values. The serum creatinine levels and BUN was measured before the start of chemotherapy and after each alternate cycle of treatment up to six times in each patient.

Table 1 Patient characteristics

Results:

Table 2shows that the SGOT levels are raised after each cycle of treatment and the difference between the SGOT levels of the patients before treatment and after subsequent cycle of treatment is significant in the patients treated with 5FU/LV (p value < 0.05). The difference in the SGPT levels of the patients from the pretreatment value is not highly significant (p value >0.05). The difference in the bilirubin levels of the patients after the sixth cycle of chemotherapy with 5FU/LV regimens is highly significant from the pretreatment level (p value < 0.05). The difference in the alkaline phosphatase levels of the patients after chemotherapy with the pretreatment value in the same patients is not significant (p value >0.05).The difference in the triglyceride levels is not significant before and after chemotherapy in the patients treated with 5FU/LV.

Table 2 Comparative changes in hepatic biomarkers in patients treated with 5FU/LV regimen

Table 3 shows that the creatinine levels are raised in patients following each subsequent cycle of treatment with 5FU/LV regimens. The difference in the serum creatinine levels after the fourth and the tenth cycle of treatment with the pretreatment levels was significant (p<0.05). The difference in the BUN levels measures before and after chemotherapy with 5FU/LV was not significant following alternate cycles of treatment.

Table 3 Comparative changes in renal biomarkers in patients treated with 5FU/LV regimen

Discussion:

The hepatocellular enzyme findings are indicative of deteriorating liver function. The levels of SGOT and SGPT both differ from the control values and point toward 5FU induced hepatic toxicity. Increase in SGOT and SGPT up to grade 2 (CTC of NIC) is reported by Hotta and colleagues (10) in a study based on clinicopathological assessment of 36 patients treated with 5FU/LV. They did not report grade 3 or grade 4 elevations in SGOT and SGPT ratio. In our data there is considerable difference in SGOT levels (mean value) after the second cycle of treatment as compared to the pretreatment levels (mean value). Similarly SGPT levels are perturbed following treatment and the difference in the SGPT levels from the pretreatment control value is statistically significant after the tenth cycle of treatment. The pooled data of all the patients cannot be used for prognostic or diagnostic assessment; however, it shows a pattern of drug induced alterations in hepatic functions. An early effect on SGOT level show mild progressive damages correlated with a prominent rise in SGPT levels. SGOT is found in cytosol whereas SGPT is in mitochondria. Any mild to moderate damage to the hepatic cells will result in a rise in SGOT levels even though SGPT levels may remain normalised. Moderate to Severe hepatic damage will give a rise in both SGOT and SGPT elevation. SGOT is located in red blood cells, kidneys, brain, skeletal muscle and cardiac tissues; hence a prompt rise in SGOT level is indicative of associated damages. SGPT is present in skeletal muscles and cardiac tissues and the serum levels are affected with myocardial and skeletal muscle damages. Cytotoxic chemotherapy is frequently associated with fatty liver disease, chemical hepatitis and reactivation of hepatitis B (11). The elevation in triglyceride levels is indicative of drug induced steatosis (fat globule deposition in hepatocytes) leading to postoperative hepatic insufficiency(8). A significant change in bilirubin from the pretreatment level is observed after the 6^th cycle of treatment. Biliary changes are detectable and persistent since the drug is excreted in the bile. Sclerosing cholangitis with elevation in alkaline phosphatase and bilirubin levels secondary to 5FU plus mitomycin therapy is reported by Fukuzumi et al (12). After intravenous administration, 5FU is converted into its active form ‘5-fluoro-deoxyuridine-monophosphate’ by anabolic reactions in the tissues. The drug undergoes catabolism primarily in the liver by reduction of the pyrimidine ring by enzymatic action of dihydrouracil dehydrogenase (13). The compound is then cleaved to urea, ammonia, carbondioxide and α-fluoro-β-alanine. The catabolic process in the liver amounts for 5FU induced hepatic toxicity. Hepatic and renal toxicity associated with 5FU is reported earlier with IV administration of 5FU (14). The risk of 5FU induced hepatic damages is increased in older patients (15). Older patients included in our study with increased post-treatment transaminase levels were more frequently presented with pruritus and hand and foot syndrome.This complexity of the situation is that altered hepatic function increases the risk of 5FU concentration (since it is catabolized in the liver cells), which in turn adds to the hepatic damage.

Creatinine clearance and blood urea nitrogen (BUN) are conventional biomarkers of renal function for convenient and cost-effective assessment (16). A detectable change in the creatinine levels of the patients ensue after the fourth cycle of treatment. Besides suggesting a decline in the renal function, it also indicates defect in hepatic functional status and progressive cachexia (muscle wasting), both of which are readily assessed in the patients during treatment. BUN levels are also affected by dexamethasone pretreatment, dehydration and azotemia besides renal function. Nephrotoxicity with 5FU chemotherapy is usually reported when it is combined with cisplatin with worsened creatinine levels (17, 18). Tubular damage induced by 5FU plus high dose leucovorin chemotherapy (similar to de Gramont’s regimen in our study) is reported by Kintzel, who also reported 50% decline in creatinine clearance in three patients (19). Chemotherapy induced renal damages are detected with abnormal creatinine and BUN levels, but in most cases the renal tubes remain intact and functional as the normal renal blood flow and GFR is reversibly attained (20). Adequate hydration and simultaneous treatment with mesna, which neutralises the toxic metabolites can effectively reduce chemotherapy induced renal damage (8).

Conclusion:

SGOT and bilirubin levels are raised after each cycle of treatment and the difference between the SGOT levels of the patients treated with 5FU/LV, before treatment and after subsequent cycle of treatment are highly significant indicative of mild to moderate progressive hepatic toxicity. Risk of clinical and subclinical renal damage is observed by a subsequent rise in serum creatinine and BUN levels. Renal toxicity marked by creatinine elevation is prominent after the fourth cycle of treatment.

A 26 year old male was brought to Emergency department with history of altered sensorium of 1 day duration. He had a 2 week history of fever prior to admission. On examination, meningeal signs were present. Fundus examination showed evidence of papilloedema and a round pale yellow spot near the optic disc (Figure 1). CT scan of head did not reveal any abnormality.

Mantoux test and HIV ELISA were negative. CSF analysis showed:  

• Glucose – 40mg/dl;  Protein: 2gm/l;   
• Cell Count: 1200cells/µl;
• Cell Type: 80% lymphocytes;
• CSF VDRL- negative;
• CSF Grams stain, India ink staining and Ziehl Neelsen staining were unremarkable.

What is the Fundus finding?

1. Roth Spot
2. Cotton Wool Spot
3. Choroidal tubercle
4. A-V malformation

Discussion:

Correct answer: 3) Choroidal Tubercle.

Intraocular tuberculosis is a rare event and occurs in 1% of all diagnosed cases of tuberculosis.¹ It occurs by haematogenous spread of mycobacterial organism. Choroidal tuberculosis is the most common initial manifestation of intraocular tuberculosis. They may be seen in 1.4% to 60% of patients with different forms of tuberculosis and are highly specific for tuberculosis. ^{2, 3}

Choroidal tubercles may be unilateral or bilateral and appear as polymorphic yellowish lesions with discrete borders. They are of 2 types, solitary tubercle or granuloma (seen in chronic tuberculosis) and choroidal miliary tubercles (seen in acute miliary tuberculosis). Their size varies from 0.4 to 5 mm and may be associated with retinal vasculitis, panuveitis, choroiditis and neuroretinitis.

When they involve macula they present with visual loss and any delay in appropriate treatment results in irreversible visual loss. Peripherally situated tubercles are asymptomatic.  Definitive diagnosis can be daunting due to difficulty in getting ocular samples for histological evaluation, however when available reveal features of granulomatous inflammation. Fundus angiography exhibits hypofluorescence in early stages and hyperfluorescence in later stages.

On treatment they heal by varying degrees of scar formation and marginal pigmentation.⁴ Untreated tubercles grow into large tumour like mass called tuberculoma.

Roth spots are retinal haemorrhages with a pale centre and are associated with bacterial endocarditis. Cotton wool spots appear as fluffy white patches on the retina and are associated with diabetes. A-V malformations are developmental vascular anomalies and appear as marked arterial and venous dilation associated with a tortuous pattern of vessels. They may have an associated bruit or chemosis of the eye.

The presence of ocular tuberculosis may be subtle. A high index of suspicion is required for its diagnosis. Delay in treatment or misdiagnosis may lead to irreversible visual loss. 

Introduction:

Insomnia is chronic inability to obtain the amount of sleep needed for optimal functioning and well-being. Insomnia has received much attention in last few decades, since it has become a growing and complex problem in our society.¹ Insomnia is defined as the chronic complaint of difficulty initiating or maintaining sleep, early awakening, and interrupting or non-restorative sleep. Furthermore, it must be accompanied by clinically significant impairment in day time function, for which there is no identifiable cause such as another sleep, psychiatric or medical disorder.¹ 

General Criteria for Insomnia^:2

1. A complaint of difficulty initiating sleep, difficulty maintaining sleep, or waking up too early or sleep that is non-restorative or poor in quality. In children, the sleep difficulty is often reported by the caretaker and may consist of observed bedtime resistance or inability to sleep inadequately.
2. The above sleep difficulty occurs despite adequate opportunity and circumstances for sleep.
3. At least one of the following forms of daytime impairment related to the night-time sleep difficulty is reported by the patient:

• Fatigue or malaise
• Attention, concentration or memory impairment
• Social or vocational dysfunction or poor school performance
• Mood disturbance or irritability
• Daytime sleepiness
• Motivation, energy or initiative reduction
• Proneness for errors, or accidents at work or while driving
• Tension, headaches or GI symptoms in response to sleep loss
• Concerns or worries about sleep 

Insomnia is prevalent condition in both the general population and in clinical practice, and it is associated with significant morbidity and mortality. It may present as the primary complaint or in association with physical or mental health problem. 

Classification:

Insomnia can be classified into two main etiologic groups:

• Primary Insomnia: When identifiable etiologies for insomnia have been ruled out, a diagnosis of primary insomnia can be made.
• Secondary Insomnia: Related to other medical disorders, mental disorders or related to known organic factors. 

Insomnia can be divided in to three types based on duration:

• Less than one month called Acute or Transient insomnia.
• One to six months called Sub-acute or Short-term insomnia.
• More than six months called Chronic insomnia. 

Following types of Insomnia recognized in The International Classification of Sleep Disorders (ICSD) second edition, Diagnostic and Coding manual:²

• Adjustment Insomnia (Acute Insomnia)
• Psycho-physiological Insomnia
• Paradoxical Insomnia
• Idiopathic Insomnia
• Insomnia Due to Mental Disorder
• Inadequate Sleep Hygiene
• Behavioural Insomnia of Childhood
• Insomnia Due to Drug or Substance
• Insomnia Due to Medical Condition
• Insomnia Not Due to Substance or Known Physiological Condition, Unspecified (Nonorganic Insomnia, NOS)
• Physiological (Organic) Insomnia, Unspecified 

Prevalence:

One third of adult population reports insomnia, 9 to 12% experience day time consequences and approximately 6% meet formal criteria for an insomnia diagnosis.³ Insomnia is more common among women, middle-aged and increases with age, shift workers and with medical or psychiatric disorders. 

Consequences:

Persistent insomnia can produce an important burden for individual and society, as evidenced by reduced quality of life, impaired daytime functioning and increased absenteeism at work, and higher health-care cost. Persistent insomnia is also associated with increased risks of depression and chronic use of hypnotics. 

Diagnosis of insomnia is based on subjective complaint of difficulties falling or staying asleep or non-restorative sleep that is associated with marked distress or significant daytime impairments. Several indicators such as intensity, frequency and duration, needs to be evaluated to assess severity of insomnia. 

Evaluation:

Insomnia is an important public-health problem that requires accurate diagnosis and effective treatment (Standard).⁴ Insomnia is a symptom of an underlying disorder or condition. The insomnia may be a problem directly related to the sleep-wake regulatory system and/or it might be associated with a comorbid psychiatric, behavioural, medical, or neurological condition.⁴ Insomnia is primarily diagnosed by clinical evaluation through a careful, detailed medical, psychiatric, and thorough sleep history (which includes assessment of sleep patterns and waking processes) (Standard).⁴ 

Treatment options:

Pharmacotherapy is currently the most common treatment modality for insomnia,⁵ but long-term use of hypnotics in chronic insomnia can become complicated by drug tolerance, dependence or rebound insomnia. Since insomnia is a chronic condition, long-term and safe treatments are warranted. Non-pharmacological options provide longer lasting benefits. 

If a cause of insomnia is identified, initial treatment should be directed at the specific factor. If insomnia persists, non-pharmacologic and/or pharmacologic interventions should be instituted. Hypnotic agents are the treatment of choice for the management of acute or transient insomnia. The expected goal is to normalize the sleep pattern within a few days to weeks. Behavioural interventions are important aspect of the treatment of chronic primary insomnia. 

Classification of evidence (Table 1) is used to determine different level of recommendations (Table 2), which is available for behavioural therapies in management of insomnia. 

Recommendations according to type of Insomnia:^{10, 11, 12} 

For both, chronic primary insomnia and secondary insomnia, the standard psychological and behavioural interventions are effective and recommended.

Recommendations for specific therapies:

1. Stimulus control therapy

Effective and recommended therapy in treatment of chronic insomnia (Standard) 

Objective is to train the insomnia patient by a set of instructions designed to re-associate the bed and bedroom with sleep and to re-establish a consistent sleep-wake schedule:

• Go to bed only when sleepy;
• Get out of bed when unable to sleep;
• Use the bed/bedroom for sleep only (no reading, watching TV etc.);
• Arise at the same time every morning;
• No napping. 

2. Relaxation training

Effective and recommended therapy in treatment of chronic insomnia (Standard) 

Aimed at reducing somatic tension (e.g. progressive muscle relaxation, autogenic training) or intrusive thoughts at bed time (e.g. imagery training, meditation) that interfere with sleep. 

3. Cognitive Behavioural Therapy (CBT) with or without relaxation therapy

Effective and recommended therapy in treatment of chronic insomnia (Standard) 

CBT includes various combinations of both cognitive as well as behavioural interventions. The cognitive component is aimed at changing patient's beliefs and attitudes about insomnia. The behavioural component may include therapies such as stimulus control therapy, sleep restriction or relaxation training. Sleep hygiene education is often also included. 

4. Sleep Restriction

Effective and recommended therapy in chronic insomnia (Guideline) 

It involves curtailing the amount of time in bed to actual amount of time spent asleep. For example, if a patient reports sleeping an average of 6 hours per night, out of 8 hours spend in bed, the initial recommended sleep window (from lights out to final arising time) would restrict to 6 hours. Periodic adjustments to this sleep window are made contingent upon sleep efficiency, until optimal sleep duration is reached. Therapy creating mild sleep deprivation, and then lengthening sleep time as sleep efficiency improves. 

5. Multi-component therapy (without Cognitive therapy)

Effective and recommended therapy in treatment of chronic insomnia (Guideline) 

• Combining stimulus control therapy, relaxation training, sleep hygiene education
• Combining stimulus control therapy, sleep restriction therapy, sleep hygiene education
• Combining sleep restriction therapy, stimulus control therapy 

6. Paradoxical intention

Effective and recommended therapy in treatment of chronic insomnia (Guideline) 

It involves instructing the patient to remain passively awake and avoid any effort (i.e. intention) to fall asleep. The goal is to eliminate performance anxiety, as it may inhibit sleep onset. This parameter is limited to sleep initiation insomnia. 

7. Biofeedback

Effective and recommended therapy in treatment of chronic insomnia (Guideline) 

It provides visual or auditory feedback to patients to help them control some physiological parameters (e.g. muscle tension) in order to seek reduction in somatic arousal. 

EEG Neurofeedback training: It is a self-regulation method that makes use of learning theory, more specifically, the paradigm of operant conditioning.⁸ While the EEG is measured; the patient receives instant feedback (visual and/or auditory) on the cortical activity of the brain. The goal of this treatment modality is to normalize the functioning of the brain by inhibiting and/or reinforcing specific frequency bands. 

Recommendations relevant to specific patient groups:

Psychological and behavioural interventions are effective and recommended in treatment of insomnia in older adults (Standard) and among chronic hypnotic users (Standard) 

Other mode of therapies:

Sleep Hygiene Education, Imagery training, Cognitive therapy. 

Insufficient evidence is available for sleep hygiene education, imagery therapy, and cognitive therapy to be an option as a single therapy. (No recommendation level) 

Sleep Hygiene Education: Please see table 3

Imagery therapy: It involves a visualization technique to focus on some pleasant or neutral images to block out unwanted thoughts before sleep. 

Cognitive therapy: Psychological methods aimed at challenging and changing misconceptions about sleep and faulty beliefs and attitudes about insomnia and its perceived daytime consequences. 

Limitations of non-pharmacological management:

• Gains in sleep onset or total sleep time are not immediately attained.
• Patient motivation and encouragement are required for success of management.
• Non-pharmacological interventions are more expensive and time-consuming.
• They require the availability of a skilled therapist. 

Results:

Psychological and behavioural therapies produce reliable changes in several sleep parameters of individuals with either primary insomnia or insomnia associated with medical and psychiatric disorders.¹⁰ A Meta-analysis indicates that in patients with primary insomnia, behavioural interventions produce improvements in sleep parameters (sleep onset latency, time awake after sleep onset (WASO), number of awakenings and total sleep time) in about 70 to 80% of patients.⁹ Behavioural interventions are more expensive, time-consuming and require the availability of a skilled therapist, but the benefits are long lasting.¹³ 

Clinical Pearl:

• Pharmacotherapy is currently the most common treatment modality for insomnia,⁵ but long-term use of hypnotics in chronic insomnia can become complicated by drug tolerance, dependence or rebound insomnia.
• Psychological and behavioural therapies produce reliable changes in several sleep parameters of individuals with either primary insomnia or insomnia associated with medical and psychiatric disorders. 
• Behavioural interventions are important aspect of the treatment of chronic primary insomnia; they should be used in every patient of Insomnia.

Evidence has consistently shown that patients with mental illness have greater physical health morbidity and mortality compared to the general population.¹ Many factors have been implicated and include a generally unhealthy lifestyle, side effects of medication, and inadequate physical healthcare.^{2, 3} Higher rates of suicide and accidents are other known risks. Psychiatric patients are more likely to smoke, have less inclination to exercise, and are prone to poor dietary habits and obesity, the latter through general inertia, the result of the adverse effects of neuroleptic medication, or increased alcohol use. Psychotropic medication is associated with impaired glucose tolerance and diabetes, metabolic syndrome, dyslipidemia, cardiovascular complications, extrapyramidal side effects and sexual dysfunction.  A broad range of clinician and organisational factors prevent access to adequate physical healthcare that in turn compounds the above problems.

Scale of physical morbidity and mortality in mental illness

Patients suffering from depression are twice as likely to develop type 2 diabetes mellitus, and the prevalence of stroke and myocardial infarction is three- and five-fold respectively higher than people without depression.⁴ A mortality rate ratio (MRR) of 2 to 3 in patients with schizophrenia or bipolar disorder is a general finding.⁵ Schizophrenia is associated with higher rates of diabetes mellitus (side effects of medication partly to blame), osteoporosis (lifestyle risk factors play a role), obesity, and cardiovascular problems^{. 2, 6, 7, 8} It has been estimated that life expectancy is reduced by at least ten years. ^{9, 10} People with learning disabilities, particularly those with concurrent epilepsy, dementia and polypharmacy, are at greater risk of developing added complications.¹¹ Eating disorders are associated with a high mortality because of physical disorders caused by anorexia/bulimia nervosa affecting other organ systems.¹² Mental illness in general is associated with an increased risk of hepatitis, human immunodeficiency virus (HIV), tuberculosis, and poor dental health. ^{9, 10}

Causes of raised physical health morbidity and mortality in psychiatric patients

Explanations for the higher morbidity and mortality in mental illness include cardiovascular and respiratory problems in addition to the increased suicide risk. Aetiological factors include adverse effects of medication (weight gain, diabetes, and dyslipidemia), lifestyle (smoking and the cost of smoking, poor diet and nutrition, lack of exercise, and obesity) and inability to access physical healthcare. Obesity, smoking and physical inactivity contribute to hypertension. Poor physical healthcare outcomes in mental illness are related to a combination of factors generally considered under the headings of patient/illness, psychiatrist/physician, and service provider/system issues.

De Hert and colleagues ^{9, 10} have outlined the factors that account for the raised physical health problems.  For instance the patient/illness factors comprised difficulty in understanding health care advice combined with the motivation required to adopt new changes in lifestyle, poor compliance with treatment, cognitive deficits, reduced pain sensitivity (induced by antipsychotic medication), poor communication and deficient social skills (seen in many cases of schizophrenia, for example) which all accounted for the shortened life-span of patients with severe mental illness (SMI). 

An additional patient/illness factor is that psychiatric symptoms may render patients less inclined to discuss physical problems. Some doctors are uncomfortable dealing with psychiatric patients because the latter may be cognitively compromised which may impair or impede a doctor’s clinical assessment. The stigma of mental illness, often the result of disparaging media coverage and negative stereotypes surrounding psychiatric patients, are other hurdles that prevent people from seeking treatment. Furthermore, psychiatric patients are less likely to see a primary care physician and therefore to receive other interventions such as screening for cancer.

Psychiatrist-related factors are characterised by an overemphasis on mental health to the exclusion of physical health, infrequent screening rates for metabolic abnormalities, omission of medical examination of patients because physical complaints frequently are part of the psychiatric presentation, poor communication with the patient and the primary care teams, a lack of awareness and perhaps adherence to treatment guidelines, insufficient medical knowledge, and erroneous, sometimes misguided beliefs about patients’ capability to change their lifestyle.^{9, 10} Even when risk factors are documented in the patient's clinical file, very little is done by way of further investigations or prevention.

Factors common to the psychiatrist and other physicians include a tendency to dismiss or interpret physical symptoms as psychosomatic, lack of good quality care, unequipped teams, insufficient assessment, and difficulties providing consistent monitoring and continuity of care. Other physician-related factors relate to problems coordinating psychiatric and medical care.^{9, 10}

Service-provision factors included a lack of clarity and consensus as to where the responsibility of physical health lies.^{9, 10} Should general practitioners (GPs) supervise the majority of patients who do not suffer from severe, enduring mental illness? Should patients with acute alcohol withdrawal symptoms be managed at home by the GP, treated in a general hospital, or admitted to a psychiatric unit? The fragmentation of medical and mental health care systems, lack of integration of services (poor or absent liaison links) and insufficient funds to resource the mental health service, limit the ability of most psychiatrists to focus beyond their own speciality. 

Service and system changes are prevalent in industrialised countries because reforms in mental health have led to reduced inpatient resources leading to shorter and infrequent hospital admissions with less time available to focus or investigate physical health problems. In the United Kingdom (UK) there is intense emphasis on community care and talking therapies, yet the management of physical health issues by community mental health teams may be poor because of inadequate training and learning. 

Recommendations to improve physical health care in psychiatric patients

Health care professionals need to be more aware of these findings in order to improve medical screening and treatment of psychiatric patients. Currently there is no evidence this is happening, with increasing concerns regarding inequalities between those with and without mental illnesses.¹³

We propose the following recommendations to promote integration between mental and physical health care:

1.    A greater effort to increase awareness of the problem among primary care and mental health care providers. The Royal College of Psychiatrists has launched a campaign called Fair Deal to highlight the importance of physical health of people with mental illness.¹ Patients still feel stigmatised and therefore psychiatrists need to boost their efforts to reduce this discrimination. The excess mortality associated with this discrimination needs to be recognised as a human rights issue.¹³

2.    Primary care providers need to change the culture of undertreating physical health in mental health patients. The National Institute for Health and Clinical Excellence (NICE) guidelines for schizophrenia and bipolar disorder highlight the importance of monitoring antipsychotics and mood stabilizers.¹⁴ The Royal College of Psychiatrists should lead by implementing the NICE guidelines for mental and behavioural conditions. 

3.    Education and training of doctors who pursue a career in psychiatry needs to be improved with mandatory trainee placements in acute medicine or neurology, regular personal development plan (PDP) courses, and training to update knowledge of recognising physical illness and the performance of basic medical tasks. The Royal College of Psychiatrists should develop a diploma in clinical psychiatry for GPs and clinicians with a specialist interest in psychiatry. The curriculum needs to be widened to include electrocardiogram (ECG) interpretation, basic endocrinology, and neurological investigations (magnetic resonance imaging and so forth). This would allow psychiatrists to develop better liaison with their fellow professionals and share responsibility with them, which undoubtedly would encourage good medical practice. 

4.    The Royal College Scoping Group’s report¹⁵ sets key standards for the physical healthcare of patients in a range of psychiatric services. It outlines the responsibilities of psychiatrists monitoring the physical health of patients, such as problems associated with adverse effects of medication. The report recommends that psychiatrists are trained and kept up to date in relevant physical health matters. These recommendationsneed to be followed.

5.    Mental health professionals should encourage patients to monitor simple measures such as weight, dietary plans, and exercise programs, with the involvement of the voluntary sector (MIND, Mental Health Foundation) where possible. Patients and carers need to be educated about the health risks associated with unhealthy lifestyles: for example, smoking and alcohol misuse may interfere with the metabolism of neuroleptic medications. Smoking cessation clinics and alcohol treatment programmes may help. Advice from dieticians about patients' nutritional requirements to offset changes in metabolism caused by neuroleptics is important. 

6.    Because of the large-scale reduction of inpatient psychiatric beds and service redesign the majority of psychiatric care provision now exists in the community. Therefore community mental health teams and psychiatric outpatient clinics need to be appropriately designed and equipped to enable proper assessment of physical health monitoring. Annual health checks from the GP would benefit patients who require long-term monitoring in the community. Screening for deleterious effects of medication for example, hypothyroidism and renal dysfunction caused by lithium, at regular intervals would be appropriate.¹⁶ It should also be made clear to psychiatrists that they should resist working in clinical settings that compromise patient care and inhibit good medical practice.

7.   Financial initiatives such as Commissioning for Quality and Innovation (CQUIN)¹⁷ may be used by commissioners to improve physical health monitoring.  As part of this process, primary care commissioners could mutually agree with mental health providers to fulfil measured targets related to such monitoring.

8.    In order to better understand the interplay between psychiatric conditions and medical complications contributing to the high physical morbidity and mortality, further studies are essential. To cite one example, we now know that psychotropic medications contribute to many physical problems (abnormal ECGs, weight gain, changes in plasma glucose) and lead to higher morbidity rates. The 'newer' generation of antidepressants and neuroleptics have not lived up to expectations and have as many untoward effects as the older drugs. Developments of newer drugs with different mechanisms of action are required, though this will take time. 

9.    The discrimination faced by people with mental illness and learning disabilities, with the accompanying excess mortality, represents a human rights issue¹³ that requires legislative changes. The Disability Right’s Commission¹⁸ has already recommended appropriate physical health care screening, for example, annual physical health checks. The government’s health inequality agenda should incorporate these conditions into its indicators of disadvantage and include mental illnesses and learning disability in the framework.

Conclusion

Traditionally the field of psychiatry involves a holistic approach in the management of patients. Unfortunately, over the decades psychiatry appears to have lost its way and therefore it is important to re-establish a more comprehensive system of treating mental illness that encompasses regular physical health monitoring. Physical morbidity and mortality in patients with mental illness is on the rise and is associated with a complex interplay of factors outlined above. The overall health care of psychiatric patients can be improved through the changes in education and training of clinicians, close liaison between primary and secondary care, implementation of recommendations by NICE and the Royal College of Psychiatrists, improved research through better funding, public health education of patients and carers, and legislative changes.

Introduction

One in four people in general and one in five people in Canada suffer from a mental disorder and only half of these individuals will seek help for their mental health.¹ Doctors have an increasingly demanding job with increasing expectations of excellence in clinical, academic and managerial roles. It seems surprising that with their rigorous training doctors have higher rates of suicide compared to the general population.² Studies have revealed that two-thirds of Canada’s physicians consider their workload too heavy, and more than half say that personal and family life have suffered because of their career choice.³ One third of Canadian physicians disagreed with a statement that their work environment encourages them to be healthy .⁴

A systematic review of mental health studies of medical students in the US and Canada found consistently higher rates of psychological distress in medical students compared with both the general population and age-matched peers .⁵ Medical students were also less likely to seek help for psychological distress than their peers. ⁶

A survey of psychiatrists and physicians in the UK found that most would be reluctant to disclose personal mental illness to colleagues or professional institutions. Their choices regarding disclosure and treatment would be influenced by issues of confidentiality, stigma, and career implications rather than quality of care.^7,8

To reduce stigma and ease physician access to mental healthcare it is important to understand and address the above issues. This will facilitate psychiatrists gaining optimized mental health as well as to improve recruitment and retention of these professionals.⁹ The objective of our study was to assess the understanding of Canadian psychiatrists to the incidence of mental illness amongst psychiatrists in comparison to the general population and also in comparison to their medical/surgical colleagues. The study also assessed the attitudes of psychiatrists towards preference for disclosure, and treatment should they develop a mental illness in addition to their own experience of mental illness.

Method

Ethics approval (Study code PSIY-336-11) from Queen’s University in Kingston, Ontario was granted. Funding was obtained from TH’s research initiation grant. A mailing list of all psychiatrists in the province of Ontario was provided by the College of Physicians and Surgeons of Ontario (CPSO) for specific use to this research project. The College of Physicians and Surgeons Ontario is a body similar to the General Medical Council (GMC) in the UK. Their role is to regulate the practice of medicine in the province of Ontario. Other provinces have their own respective College of Physicians and Surgeons. In the remainder of the text the term ‘psychiatrist’ refers to consultant psychiatrist.

The list obtained from the CPSO did not include approximately 10% of psychiatrists who opted out of having their postal details released for research purposes. In total 1231 psychiatrists were sent a survey package. This package included a covering letter, a 2-page questionnaire, and a stamped return addressed envelope. Consent was assumed based on taking part in the survey. The 10-item questionnaire was based on a review of the literature, previous research, and discussion with colleagues. It comprised broadly of three sections. The first collected information on the respondents’ perception of prevalence of mental illness in psychiatrists in comparison to the general population and then in comparison with other medical/surgical specialties. The second required psychiatrists to identify to whom they were most likely to disclose a mental illness and reasons for non-disclosure. The third asked psychiatrists their preference of treatment in both an outpatient and inpatient setting. The identifiable information requested was the amount of experience the respondent had as a psychiatrist and whether they had experienced mental illness in the past. A free-text box was included at the end for comments and complete anonymity was maintained. Psychiatrists were divided into 3 groups: Group 1 (less than 5 years of experience as a psychiatrist), Group 2 (5-10 years of experience) and Group 3 (greater than 10 years of experience).

Analysis

A series of two-sample chi-square tests (χ²) were conducted to examine associations between certain categorical variables. In cases where 20% of contingency cells were <5 or where any cell=0, Fisher’s Exact test was used. Phi (φ) or Cramer’s V (for associations >2x2) were used as measures of effect size, these provide an association coefficient between 0 and 1. All analyses were done using SPSS 19.

Results

Of the 1231 questionnaires sent to doctors 487 were returned, a response rate of 39.6%. The respondents were placed into three groups: those in attending for <5 years (55, 11.3%), 5-10 years (53, 10.9%) and >10 years (369, 75.8%). The frequency of responses to all questions, both overall and as a function of attending group are shown in Table 1.

Table 1. Responses to all questions and comparisons between attending groups. Discrepancies between the overall column and the sum of the attending group columns are due to missing cases in responses to the attending group question.

Perception of the incidence of mental illness

Just over half of respondents disagreed that the incidence of mental illness was higher in doctors than the general population (247, 50.7%). Just over a quarter (124, 25.5%) agreed and just under a quarter replied ‘don’t know’ (116, 23.8%). As can be seen in Table 1, the pattern of responding was similar across all attending groups on this question (χ²=5.92; df=4; p=.205; Cramer’s V=.08). Most disagreed that psychiatric illness was greater in medical/surgical professionals than in psychiatrists (285, 58.5%), a small minority agreed (37, 7.6%). Again the attending groups responded similarly on this question (χ²=7.06; df=4; p=.133; Cramer’s V=.09). Nearly a third of respondents (151, 31.0%) claimed to have experienced a mental illness, and once more the attending groups did not differ significantly in their responses to this (χ²=1.12; df=2; p=.57; Cramer’s V =.05).

Disclosure of mental illness

Respondents would be most likely to disclose their mental illness in the first instance to family and friends (204, 41.9%) although many would instead prefer to disclose to their family physician (153, 31.4%). Relatively few would disclose to a colleague (54, 11.1%) in the first instance or to a mental health professional (32, 6.6%), very few would choose no-one (15, 3.1%) and the clergy was the least endorsed option (3, 0.6%). When considering only the three most popular response options (family/friends, family physician, and colleague) the three attending groups responded similarly (χ²=6.63; df=4; p=.157; Cramer’s V=.09). When asked about the most important factor affecting the decision not to disclose, the most common response was career implications (168, 34.5%). However stigma (114, 23.4%) and professional standing (80, 16.4%) were also reasonably common responses.

Again, when including only the three most popular disclosure choices in the analysis, there emerged an association between choice of whom to disclose and factor affecting disclosure (χ²=12.52; df=6; p=.051; Cramer’s V=.13) (see Table 2). Those who would choose to disclose to their family physician or to family/friends were more likely to cite stigma as a factor influencing their choice than those who would choose to disclose to colleagues. Those who would disclose to colleagues would be more likely to cite professional standing as a factor influencing their choice compared to those who would disclose to their family physician or to their family/friends. There was no association between choice of whom to disclose and previous experience of mental illness (χ²=1.22; df=2; p=.545; Cramer’s V=.05).

Table 2. Preferences for disclosure and the factors influencing that preference.

Treatment for mental illness

When considering out-patient treatment, the majority of respondents would opt for formal professional advice (365, 74.9%). A small proportion would choose informal professional advice (83, 17.0%) and very few would self-medicate (25, 5.1%) or have no treatment (9, 1.8%). With regard to in-patient treatment, the majority would opt for an out of area mental health facility (370, 76.0%). Only just over a quarter of respondents (130, 26.7%) claimed that quality of care would influence their choice of in-patient care, just over half would be most concerned about confidentiality (257, 52.8%) There was a strong association between in-patient preference and the factor influencing that preference (Fisher’s Exact=228.25; p<.001; Cramer’s V=.70). As shown in Table 3, those who would choose an out of area facility, were much more likely to cite confidentiality and stigma as factors influencing their choice, than those who would choose a local facility. Conversely, those choosing a local facility were more likely to cite quality of care and convenience as influencing factors.

Table 3. In-patient treatment choice and the factors influencing that choice.

There was an association between attending group and out-patient preference (Fisher’s Exact=12.00; p=.042; Cramer’s V=.13). As can be seen in Table 1, the >10 years group would be more likely to select informal advice than the <5 years group, but the >10 years group were less likely to self-medicate than the <5 years group. The >10 years group responded similarly to the 5-10 years group with regard to self-medication. There was also an association between attending group and in-patient preference (χ²=12.66; df=2; p=.002; Cramer’s V=.16). The >10 years group, although still largely in favor of out of area care, would be more likely than the other two groups to opt for local care. There was also a significant association between attending group and the factors influencing in-patient choice (Fisher’s Exact =25.335; p=.001; Cramer’s V=.16). As shown in Table 1, the >10 years group would be more influenced by quality of care and less influenced by confidentiality than the other two groups.

Finally, previous experience of mental illness was not associated with in-patient choice (χ²=0.542; df=1; p=.462; φ=-.04), but it was associated with out-patient choice (χ²=11.51; df=3; p=.009; Cramer’s V=.16). As Table 4 shows, although both groups are more likely to opt for formal over informal advice, this pattern is more pronounced in the group who have had mental illness, than in the group who have not previously had mental illness.

Table 4. Previous experience of mental illness and out-patient treatment preference.

Discussion

This is the first study to assess the attitudes of Canadian psychiatrists to becoming mentally ill themselves. As this study was carried out in one province of Canada and the results cannot be generalized across the country. There is a significantly large scope of research potential in this area especially among psychiatric residents and other healthcare professionals .¹⁰

Physician Impairment is any physical, mental or behavioral disorder that interferes with the ability to engage safely in professional activities.¹¹ Impairment among medical practitioners and psychiatrists in particular is a significant problem characterized by chronicity, under reporting and in many cases, poor outcomes.¹² However early detection, intervention and treatment programs that are more sensitive to the needs of impaired practitioners, that are more continuous, better structured, and rehabilitation and recovery focused may be more likely to produce a positive outcome. ¹³ It is extremely important to remember and advocate that although a physician may be mentally ill he/she is not necessarily impaired.

It is concerning that stigma continues to play a role in psychiatrists’ decision making process to obtain mental healthcare. This is consistent with the findings of a survey in the USA which showed that half of all psychiatrists with a depressive illness would self-medicate rather than risk having mental illness recorded in their medical notes.¹⁰ Both entertainment and news media provide a dramatic and distorted image of mental illness that emphasize dangerousness, criminality and unpredictability.¹⁴ With this increased stigma doctors subsequently are concerned whether to disclose a mental health problem to their Licensing Boards for fear of being discriminated.¹⁵ Studies of US medical licensing bodies have demonstrated a trend towards increasing stigmatizing approaches ^16-19 and the concern is whether there is a similar trend in Canada.⁹ Most psychiatrists in Canada are not aware what to expect from provincial colleges once their mental illness is disclosed and as a result tend to expect the worst. More work is needed by psychiatrists to inform the Provincial Colleges on physician mental health. Only then can the Provincial Licensing Colleges do more to assure physicians that the recovery model of treatment applies to them as it does other psychiatric patients.

The gap however continues to lie between ‘I need help’ and active psychiatric management. Psychiatrists will be well aware of the profound impact that such illnesses can have on a person’s personal and professional competency. However to reflect it on oneself can at times be met with denial in the first instance. Dr. Mike Shooter (ex-President of the Royal College of Psychiatrists, UK) suffered from depression and he highlights the need to speak out and combat stigma. He points out the need to seek treatment early and how not doing so can adversely affect the doctor-patient relationship.²⁰ For some however the fear of stigmatization by health professionals for health professionals can lead to very tragic consequences. Dr. Suzanne Killinger-Johnson was a family physician with a psychotherapy practice in Toronto. She suffered from postpartum depression and in November of 2000 she jumped in front of a subway train cradling her son. Her son died instantly and Dr. Killinger-Johnson died 9 days later.²¹

Over the past 15 years a greater understanding has developed on the incidence, stressors and complications of physician mental illness. ²² The CPA published its first position paper on the mentally ill physician as early as 1984 with the latest version in 1997 currently under review. ²² The Canadian Medical Association should be congratulated on the most comprehensive strategy document for mentally ill physicians. Physician Health Matters - A mental health strategy for physicians in Canada was published by the CMA in February 2010. In addition to outlining the mental health of medical students, residents and physicians it addresses the current gaps in services and strategic direction needed to achieve ‘optimal mental health for all physicians’. This sets out the necessary groundwork for institutions to implement based on current evidence. In Canada there was the inauguration of the position of ‘The Bell Mental Health and Anti-Stigma Research Chair’ with Queen’s University in February 2012. ²³ This position was offered to Dr. Heather Stuart, Professor of Community Health and Epidemiology. Stigma is a social process characterized by exclusion, rejection, blame or devaluation resulting from an adverse social judgment about a person or group. ²⁴ There is a cultural pressure amongst physicians not to be sick so that one can provide care resulting in physicians unfortunately trying to control their own illness and treatment. ²⁵ This concept is exacerbated for mental health issues and the stigma is considerably attached to physicians acknowledging mental health issues or illness, as well as seeking help. ²⁶

Over the past decade the physician health community has been working to destigmatise physician mental health and to provide support services in this regard. All Canadian provinces have Physician Health Programs (PHPs) to help physicians with mental health difficulties. Referrals can be from physicians, families, colleagues, and self. ⁹ Physicians with psychiatric or drug dependence problems are referred from outside the PHP though the PHP (depending on the province) may or will be involved in monitoring the physician.

One of the most important factors influencing where a doctor is treated is the issue of confidentiality. ⁸ At present in Canada many hospitals are either switching or have switched to electronic patient records. Patient data in an electronic environment will be accessed from multiple portals by different professionals. This potentially poses serious concerns for psychiatrists if they have significant concerns around confidentiality of their record. A mechanism by which patients can access a list of professionals who have accessed their information may alleviate some concern regarding confidentiality.

Conclusions

Education surrounding mental illness in physicians needs to begin in medical school. Medical students require more assurance that seeking help for psychological problems will not be penalized. Junior doctors are receptive to education on physician impairment and substance misuse and this should be a mandatory component of their training. ²⁷ Education and training of medical students and psychiatric residents to assess doctors as patients would make this scenario less taboo than it is currently perceived.

CPSO in liaison with relevant partners must develop a clear and concise document outlining steps the CPSO will take in helping the mentally ill physician. This document must be clearly advertised on the CPSO website to ease access and would reduce the catastrophizing interpretation psychiatrists (and physicians) may make to the CPSO’s involvement with the mentally ill physician. By the CPSO taking a lead this will prove a stimulus for other provincial licensing colleges to follow suit.

The bridge from ‘I need help’ to ‘I am getting help’ is paved with multiple barriers. By addressing some of the concerns raised by psychiatrists will help the psychiatrist easily cross over.

Introduction:

Candida species is a leading cause of nosocomial infections and the most common fungal infection in intensive care units.  Candida infection ranges from invasive candidal disease to blood stream infections (candidaemia).  The incidence of Candida infection has been rising over the past two decades, particularly with the use of immunosuppressive drugs for cancer and HIV^1,2,3 , and most of these infections occur in ICU settings.⁴  Candida infection is associated with high mortality and morbidity. Studies have shown that mortality attributable to candidaemia ranges from 5 to 71% depending on the study. ^5.6.7Candidaemia is also associated with longer length of hospital stay and higher cost of care.

Early recognition of Candida BSI has been associated with improved outcome. Candida sepsis should be suspected in a patient who fails to improve and has multiple risk factors for invasive and bloodstream Candida infection. A variety of risk factors identified for candidaemia include previous use of antibiotics, sepsis, immunosupression, total parenteral nutrition, central venous line, surgery, malignancy and neutropaenia. Patients admitted to ICU are frequently colonised with Candida species. The role of colonisation in Candida blood stream infection and invasive candidal disease has always been debated. Few studies support the use of presumptive antifungal treatment in ICU based on colonisation and number of sites colonised by Candida. The NEMIS study has raised doubt about this approach of presumptive treatment.  The Infectious Disease Society of America (IDSA) 2009 guidelines identify Candida colonisation as one of the risk factors for invasive candidiasis, but warn about the low positive predictive value of the level of Candida colonisation. ⁸ We conducted a retrospective cohort study in our medical ICU to identify risk factors for Candida blood stream infections including the role of Candida colonisation.

Hospital and Definitions:

This study was conducted at Interfaith Medical Center, Brooklyn, New York.  It is a 280 bed community hospital with 13 medical ICU beds. A case of nosocomial Candida blood stream infection was defined as a growth of Candida Species in a blood culture drawn after 48 hours of admission. Cultures in our hospital are routinely done by the Bactec Method – aerobic and anaerobic cultures. Cultures are usually kept for 5 days at our facility and if yeast growth is identified, then species identification is done. In our ICU it is routine practice to do endotracheal culture and urine culture for all patients who are on mechanical ventilator supports and failing to improve. In patients who are not mechanically ventilated, it is routine practice to send sputum culture and nasal swabs to identify MRSA colonisation.

Study Design:

This study was a retrospective cohort study. We retrospectively reviewed all patients’ charts admitted to our medical ICU from 2000 to 2010 which stayed in the ICU for more than 7 days, irrespective of their diagnosis. Data were collected for demographics – age and sex. Data were also collected for risk factors for candidaemia – co-morbidities (HIV, cancer, COPD, diabetes mellitus, end-stage renal failure (ESRF)), presence or absence of sepsis, current or previous use of antibiotics, presence of central venous lines, steroid use during ICU stay, requirement of vasopressor support and use of total parenteral nutrition (TPN). Culture results for Candida including species identification were obtained for blood, urine and endotracheal aspirates.

Statistical Methods:

Patients were divided in two groups based on presence or absence of Candida BSI. Demographic data and risk factors were analysed using the chi square test to look at the difference between the two groups. Endotracheal aspirates and sputum cultures were combined to create a group with Candida respiratory tract colonisation. Binary logistic regression with forward likelihood ratio method was used to create models. Different models were generated for risk factors. Interactions between antibiotic use, steroid use, vasopressor support and sepsis were analysed in different models. Interactions between urine cultures and endotracheal aspirates/sputum cultures were also analysed by a different model. The model with the lowest Akaike information criterion (AIC) was chosen as the final model. The candidaemia risk score was calculated based on this final model to predict the risk of Candida BSI. Receiver operating curve (ROC) analysis was used to select the best cut-off value for the candidaemia risk score. Candida species in urine and endotracheal aspirates were compared with Candida species in blood culture using the kappa test. Data were analysed using SPSS statistical analysis software version 18.

Study Results:

A total of 1483 patients were included in the study.  56 patients (3.77%) had a blood culture positive for Candida species. Table 1 demonstrates demographic characteristics of the study population.  There were no significant differences in the both groups for age, sex, diabetes mellitus, COPD, HIV, cancer and ESRF. As demonstrated in the table, 82.1% of patients in candidaemia groups recently used or were taking antibiotics as compared to 39.6% of patients in groups with no candidaemia. The P value was significant for this difference.  Similarly, 71.4% of patients in the group with candidaemia had sepsis as compared to 30.6% in the other group with a P value of 0.000. Use of vasopressor (severe septic shock) was different between two groups – 23.2%  and 10.1%, P value of 0.004. Steroid use, central lines and total parenteral nutrition use was higher in the candidaemia group as compared to the group without candidaemia. Similarly the rate of positive Candida cultures in urine and endotracheal aspirates was higher in the candidaemia group as compared to the group without.

Table 2 shows that 57.1% of Candida BSI were caused by C. Albicans, 30.4% by C. Glabrata and 12.5% by C. Parapsilosis. This incidence rate of species is similar to that found in other studies. Table 3 shows the two models with the lowest AIC value. The only difference between these two models was antibiotic use- previous or current use of antibiotics compared to current use of antibiotic in sepsis. Table 4 shows that when multifocal site positivity (urine and endotracheal culture) were used in the model, the AIC value increased significantly. This means that when multifocal sites were used in place of individual sites for the model, good amounts of information were lost and this model did not have good predictive value as compared to the model where individual sites are used for prediction of candidaemia. The model with lowest AIC was chosen as the final model. Binary logistic regression analysis with forward conditional analysis showed that only TPN, central venous line, previous or current antibiotic use, endotracheal aspirate culture positivity for Candida species and urine culture positive for Candida species were included in a statistical significant model. The final model had a P value of 0.000.  Odds ratio with 95% confidence intervals and respective P values for all these risk factors are shown in Table 5.  Age greater than 65 years, sex, sepsis or septic shock, co-morbidities and steroid use were not significant risk factors for candidaemia.

From this model, the candidaemia risk score calculated would be: Candidaemia risk score = 1.184 for previous or current antibiotic use + 0.639 for presence of central venous line + 1.186 for total parenteral nutrition + 0.760 for positive endotracheal culture for Candida + 1.255 for positive urine  culture for Candida.

Table 6 shows the relationship between the Candida strain identified in endotracheal/sputum culture to that in blood culture. Similarly, Table 7 shows the relationship between the Candida strain identified in urine culture and that in blood culture. Strains identified in endotracheal aspirate culture had a very high value for the Kappa test and urine culture had a moderate value for agreement by the Kappa test. Thus, it can be inferred that Candida strain identified in blood culture was very similar to that identified in urine or endotracheal culture.

Table 1: Demographic characteristic of study population

Table 2: Candida strains responsible for Candida blood stream infection

Table 3: Models with lowest two AIC

Table 4: Model with 2 sites positive for Candida

Table 5: Odds ratio with 95% confidence interval for risk factors for candidaemia

Table 6: Endotracheal aspirate culture in candidaemic patients

Table 7: Urine cultures in candidaemic patients

Discussion

Candida is the most common nosocomial fungal infection in the ICU. Candidaemia accounts for approximately 5-8% of nosocomial BSI in the hospitals in the US.^9,10,11 It accounts for approximately 50-75% of the cases of invasive fungal infection in the ICU^12,13 and its rate varies from 0.2-1.73 per 1000 patient days.^9,14,15 In a study done by Theoklis et al., candidaemia was associated with a mean 10.1 day increase in length of stay and a mean $39,331 increase in hospital charges.¹⁶ A study of 1,765 patients in Europe found that Candida colonisation was associated with increased hospital length of stay and increase in cost of care by 8000 EUR.¹⁷ ICU patients are at increased risk of infection because of their underlying illness requiring ICU care, immunosuppressant use, invasive or surgical procedures and nosocomial transfer of infections. A number of risk factors have been identified in different studies. In a matched case-control trial, previous use of antibiotic therapy, Candida isolated at other sites, haemodialysis and presence of a Hickman catheter were associated with increased risk of candidaemia.¹³ Similarly age of more than 65 years, steroid use, leucocytosis and prolonged ICU stays were risk factors for Candida BSI in 130 cases.¹⁸ Surgery, steroids, chemotherapy and neutropaenia with malignancy are the other identified risk factors.¹⁹

Candida BSI has a very high mortality rate. The attributable mortality varies from 5-71% in different studies.^5,12,16,20 Even with treatment, there is high mortality as demonstrated in a study by Oude Lashof et al where out of 180 patients treated for candidaemia, 33% died during treatment and 55% completed treatment without complications.²¹ Risk factors for increased mortality in patients receiving antifungal treatment are delayed Candida antifungal treatment or inadequate dosing.²² Multivariate analysis of 157 patients with Candida BSI, APACHE II score, prior antibiotic treatment and delay in antifungal treatment were independent risk factors for mortality with odds ratio of 1.24, 4.05 and 2.09, respectively.²³ Delayed treatment is also associated with increased fluconazole resistance as compared to early treatment and preventive treatment.²⁴ Inadequate antifungal medication dose and retention of central venous catheters were also associated with increased mortality in a study of 245 Candida BSI, with adjusted odds ratios of 9.22 and 6.21, respectively.^25,26

Candida albicans accounts for 38.8-79.4 % of the cases of Candida BSI. C. Glabrata is responsible for 20-25% of cases of candidaemia and C. tropicalis is responsible for less than 10% of cases of candidaemia in the US.^9,20  ICU patients are frequently colonised with different Candida species. Candida colonisation can be from either endogenous or exogenous sources. Candida colonisation rates vary with the site- tracheal secretion (36%), throat swabs (27%), urine (25%) and stool (11%).²⁷ Candida colonisation increases with the duration of the stay, use of urinary catheters and use of antibiotics. ^28,29,30

The role of Candida colonisation in Candida BSI is frequently debated.  Some studies have suggested that Candida colonisation of one or more anatomical sites are associated with increased risk of candidaemia.^31,32,33,34 Typically, 84-94% of the patients developed candidaemia within a mean time of 5- 8 days after colonisation according to two studies.^35,36  In another study, only 25.5% of colonised patients developed candidaemia.³⁷ Similarity between strain identified in blood culture and that identified at various colonising sites was observed in one study.³⁸  Candida colonisation by exogenously acquired species has also been implicated as a cause of candidaemia.³⁹ In one study, 18-40% of cases of candidaemia were associated with clustering defined as “isolation of 2 or more strain with genotype that had more than 90% genetic relatedness in the same hospital within 90 days.” ⁴⁰ Similar correlations for clusters are also noted for C. tropicalis candiduria⁴¹ and for C. Parapsilopsis.⁴² In a prospective study of 29 surgical ICU patients colonised with Candida, the APACHE II score, length of previous antibiotic therapy and intensity of Candida colonisation was associated with a significant risk of candidaemia.  The Candida colonisation index calculated by non-blood body sites colonised by Candida over the total number of distinct sites tested for patients, was associated with a 100% positive and negative predictive value of candidaemia.²⁹ Other studies do not support Candida colonisation as a risk factor for candidaemia. In a case-control study of trauma patients, only total parenteral nutrition was associated with an increased risk of candidaemia. Candida colonisation, steroid use, use of central venous catheters, APACHE II score, mechanical ventilation for more than 3 days, number and duration of antibiotics, haemodialysis, gastrointestinal perforation and number of units of blood transfused in first 24 hours of surgery. were not significant risk factors for candidaemia.⁴³ NEMIS study found that in a surgical ICU, prior surgery, acute renal failure, total parenteral nutrition and triple lumen catheters were associated with increased risk of candidaemia; the relative risk for each risk factor being 7.3, 4.2, 3.6 and 5.4, respectively. Candida colonisation in urine, stool or both were not associated with increased risk of candidaemia.¹⁵

The effect of Candida colonisation of the respiratory tract on candidaemia and on mortality and morbidity is unclear. In a retrospective study of 639 patients, Candida respiratory tract colonisation was associated with increased hospital mortality (relative risk of 1.63) and increased length of stay (median increase of 21 days).³⁰ In a study of 803 patients by Azoulay et al., respiratory tract colonisation was associated with prolonged ICU and hospital stays. These colonised patients were at increased risk of ventilator-associated Pseudomonas pneumonia, with an odds ratio of 2.22.⁴⁴ However, in a postmortem study of 25 non-neutropaenic mechanically ventilated patients, 40% of the patients were colonised with Candida, but only 8% had Candida pneumonia.^45,46  Jordi et al. found that out of 37 patients, definite or possible colonisation was found in 89% of patients and only 5% of cases were defined as Candida BSI.⁴⁷.The effect of candiduria is also ill defined. Candida colonisation in urine has been implicated as a risk factor in certain studies. In a study done by Bross J et al., central lines, bladder catheters, 2 or more antibiotics, azotaemia, transfer from another hospital, diarrhoea and candiduria were significant risk factors for candidaemia. Candiduria had an odds ratio of 27 for development of candidaemia.⁴⁸ Similar findings about candiduria were noted by Alvarez-Lerma et al.⁴⁹

IDSA recommends starting empirical antifungal treatment for high risk neutropaenic patients who fail to improve on antibiotics after 4 days. Recommendation to start empirical antifungal therapy in low-risk neutropaenic patients and non-neutropaenic patients are not made by IDSA because of low risk of candidaemia.⁸ However, early detection of Candida BSI is vital because of increased mortality associated with delayed antifungal treatment and failure to remove central venous lines. Early detection of Candida BSI in a colonised patient can be facilitated by using a score based on the risk factors.^50,51Similarly, b-D glucan assays can be used in patient colonised with Candida, to determine Candida BSI and need for antifungal treatment.⁵² Combined used of such risk factor identification systems and b-D glucan assays will help to detect candidaemia in earlier stages and will decrease mortality. Our study suggests that total parenteral nutrition, previous or current antibiotic use, central lines, candiduria and respiratory tract colonisation are risk factors for Candida BSI. With the help of our candidaemia risk score system, a score of more than 2 is associated with a higher risk of Candida BSI. This risk factor scoring system along with b-D glucan assays can be used to detect Candida BSI in earlier stages.

Conclusion:

Our study suggests that urine or respiratory tract colonisation is associated with an increased risk of Candida BSI, along with total parenteral nutrition, central venous lines and previous or current antibiotic use. We identified a scoring system which can be used along with a b-D glucan assay to detect candidaemia earlier.

Introduction

Routine pulse palpation is the recommended screening method to detect asymptomatic atrial fibrillation (AF) in clinical practice¹. Since this is part of the blood pressure (BP) measurement technique when using the Riva Rocci (mercury) device or the aneroid device, most patients are evaluated for rhythm irregularity while checking their BP, and, if pulse isn’t palpated, heart rhythm can be evaluated through auscultation of Koroktoff’ sounds. According to the European Community law (2007/51 CE; 2007 September 27^th), the mercury sphygmomanometers should not be sold any more, therefore aneroid or automatic devices will replace them in a few years. Recently new devices with embedded algorithms to detect irregular heart beat and possible AF have been commercialised. Whether the switch from Riva-Rocci or aneroid sphygmomanometer to this device will affect detection of AF in usual care is unknown. We explored this issue using a retrospective, naturalistic observation of a group of GPs who abandoned the “old” Riva-Rocci or the aneroid sphygmomanometer and adopted this new device.

Methods

In September 2011 the members of the Italian College of General Practitioners based in Bologna (a medium size city in Central Italy) decided to standardize their office BP measurements. They received an unconditional grant for 30 automatic upper arm blood pressure monitors (Microlife- Afib ®) to be used in office by the GP him/herself. This device embeds an algorithm that calculates the irregularity index (standard deviation divided by mean) based on interval times between heartbeats; if the irregularity index is above a certain threshold value, atrial fibrillation is likely to be present and an atrial fibrillation icon is displayed on the screen. The 30 general practitioners who received the device agreed to a later proposal to examine their database to evaluate detection of new AF patients. They all had the same professional software (Millewin®), and used an automatic extraction. All the patients with recorded diagnosis of hypertension were identified, then BP recording and AF diagnosis were extracted before (365 days preceding the use of Microlife) and after (4 months since starting the use of Microlife) the adoption of the automatic devices. The proposal to examine AF detection was made after four months after they received the devices, therefore the GPs weren’t aware of this study during the usual professional activity. This study was also neither planned nor known by Microlife. Fourteen other GPs, who were using the traditional device, volunteered to provide the same data extraction from their personal database.

Results
The 30 participants GPs cared for 48,184 individuals, 12,294 (25.5%) of whom had hypertension (mean age 69.9±13.4). The 16 control GPs cared for 23,218 patients, 5,757 (24.8%) with hypertension (mean age 69.7±13.6). The four-monthly AF detection rate for the original group and the control group is reported in table 1. All the new detected AF were then confirmed on ECG. Statistical analysis was made with the chi-square (χ²) test.

Table 1: Four-monthly AF detection rate in the original GP group and in the control group*

*‡ Use of the traditional device: original group vs controls: p NS ( χ² = 3.0421, df 1)
** use of the automatic device (other quarters use of traditional device)
**‡‡ Original group: use of the automatic device vs traditional device in AF detection: p < 0.005 (χ ² = 9.487, df 1)

Discussion

Atrial fibrillation can be difficult to diagnose as it is often asymptomatic and intermittent (paroxysmal). The irregularity of heart rhythm can be detected by palpation of the pulse. It may therefore be detected in patients who present with symptoms such as palpitations, dizziness, blackouts and breathlessness, but may also be an incidental finding in asymptomatic patients during routine examination. The diagnosis must be confirmed with an ECG, which should be performed in all patients, whether symptomatic or not, in whom atrial fibrillation is suspected due to the detection of an irregular pulse. Heart rhythm should be evaluated while measuring BP with traditional sphygmomanometers, while this information may be lost with automatic devices, therefore the use of automatic devices with algorithms which can detect possible AF is an appealing choice. The hypothesis that these devices are equal or superior to systematic pulse palpation is currently under investigation by NICE². At the moment the consequences of switching from the classical Riva-Rocci devices to these new ones in usual care isn’t known. The AF opportunistic screening in people aged > 65 leads to a 1.63% detection rate while usual care has a detection rate of 1.04%, very similar to that observed in our hypertensive population (1.13%)³. Our data show that, at least in the short term, switching from the usual device to an automatic device with algorithm for irregular beat detection increases the identification rate of previously unknown AF in the hypertensive population. While waiting for a formal appraisal, GPs who wish or must renounce to their “old” Riva-Rocci can use this device implementing their “usual care” performances.