Ventricular Septal Defect in Eight Holstein Calves in a Large Dairy Herd

Introduction

In this clinical case series report, we aimed to present clinical findings concerning congenital ventricular septal defect (VSD) in a commercial dairy herd in Iran (Behroozi Dairy Complex, approximately 3000 dairy cattle, Tehran, Iran) and to differentiate between VSD and respiratory diseases in Holstein calves. The VSD is an abnormality in both human and animal hearts in which the heart wall (septum) that divides the heart into two separate parts (left and right ventricles) is not fully developed during embryogenesis [1]. As a result, a hole is formed between heart ventricles leading to disturbed and abnormal blood flow into the heart that cause heart failure. Genetic background has been proposed as a main cause of VSD in humans. However, in a recent study [2], it was concluded that maternal stressful life had a significant role in the development of heart disorders especially VSD in offspring.

Case Presentation and Discussion

In previous reports concerning VSD in Holstein calves, only one calf has been identified with VSD [3,4]. However, according to our observations in a large dairy herd, we suggest that VSD occurs more frequently and that it could be confused with respiratory diseases at least in some cases. In the current case report, eight Holstein calves (5 females and 3 males) were diagnosed initially for respiratory diseases but were further examined for the probability of heart defects. Consequently, the VSD was diagnosed and observed by postmortem necropsy in all 8 calves. The Figures 1 & 2 illustrate the hole position with different sizes obtained from culled/dead calves with VSD in a large dairy farm (Behroozi Dairy Complex, approx. 3000 dairy cattle, Tehran, Iran). The calves diagnosed with VSD ranged from 1 to 90 days of age, indicating that this phenomenon occurs in different young ages. As the VSD is a congenital disorder, its severity can be affected by the hole diameters. This implies that calves with a smaller hole in the septum might live without any problem unless the hole becomes large enough to seriously compromise the heart function as calf ages. Therefore, disorder detection and calf culling, or death may occur in a variety of ages. Like the age, the VSD was not sex-dependent either and it occurred in both female and male calves. Moreover, exploring parity in the incidence of VSD revealed no differences between cows or heifers.

Figure 1: The hole position (VSD) is illustrated when observed in culled/dead calves in a large dairy farm (Behroozi Dairy Complex, Tehran, Iran).

Figure 2: The hole position with different size in another case of VSD in another calf (Behroozi Dairy Complex, Tehran, Iran).

As noted, the symptoms of VSD were primarily similar to those of the respiratory diseases. Hyperpnea, lethargy, anorexia and poor growth are common clinical symptoms of VSD. Clinically, substantial alterations occur in heartbeat frequency and sound in the VSD cases. For instance, the heart beats faster and a thrill can be detected when the right or left side of the thorax is palpated. The heart auscultation showed an audible murmur in all affected calves with different degrees of VSD. The body temperature was normal in the VSD cases, whereas in respiratory diseases, the body temperature is almost high (> 39.3 °C). As such, the early diagnosis of VSD in calves can be helpful in managing these animals and provide an opportunity to distinguish it from respiratory diseases. As a result, the useless antibiotics therapy should be avoided. Finally, the right calf culling time can be decided upon. As noted above, mothers exposed to stressful life during pregnancy had higher risks of VSD development in offspring. It has been reported that maternal lifestyle as well as excessive body mass possess potential roles in increasing congenital heart defects in babies [5]. Suboptimal calf welfare may occur when dams are exposed to stresses and diseases during pregnancy [6]. Overall, it is suggested that gestation is a critical phase for both dam and fetus and that all pressures must be minimized during this period. Overcrowding, hyperthermia, and nutritional deficiency are the most common stressors in ruminant farms worldwide.

As a result, optimizing the pregnant and dry cow environment by reducing stress might reasonably decrease congenital disorders, and hence, improve the productivity and sustainability of commercial dairy herds.

Conclusion

Eight cases of the Ventricular Septal Defect (VSD) were diagnosed and reported in the present study in a large dairy herd in Iran. The VSD is a common heart abnormality leading to culling or death of young calves. Hyperpnea, lethargy, and poor growth are its most common symptoms, but they should be differentiated from the similar symptoms in respiratory diseases. Palpation of the right side of thorax would be useful for the early diagnosis of VSD. Controlling stress in late gestation and attention to herd genetics programs could be helpful in minimizing congenital heart problems. Consequently, preventing calf culling or death will benefit the commercial dairy herds’ economy.

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The Importance of Just in Time (JIT) Methodology and its Advantages in Health Care Quality Management Business – A Scoping Review

Introduction

The logistics management of Modular integrated construction (MIC) (Mohamed Hussein, et al. [1]) has always been a major barrier to the wider adoption of (MIC). Nonetheless this challenge can be tackled by the application of lean techniques namely justin- time (JIT). Numerous studies have identified and evaluated the critical factors (CFs) required to implement JIT. The results indicate that all the 42 CFs are important for applying JIT of (Mohamed Hussein, et al. [1]) which seven are highly significant for successfully implementing JIT in (MIC). The results of the randomized trial strongly support (Christopher M, et al. [2]) the efficacy of just-in-time evidence-based reminders as a means of changing clinical practice among home health nurses who are geographically dispersed and spend much of their time in the field. Both the basic and the augmented interventions greatly increased the practice of evidence-based care according to patient records in the areas of patient assessment and instructions about HF disease management. While not all results were statistically significant at (Christopher M, et al. [2]) conventional levels intervention effects were positive in virtually all cases and effect magnitudes frequently were large (Figure 1).

Figure 1: Worldofagile.com [32].

The JIT and stockless approach to provider supplier relationships (Lynch D [3]) has proven to be a win-win proposition for the partners that have implemented it in many manufacturing industries and health care organizations as well. This strategy will fundamentally impact the entire cost structure within the hospital supply distribution chain. The sweeping changes the health care industry experienced during the 1980s are leading creative materiel managers to seize the initiative to improve the current operating (Lynch D [3]) costs of their hospitals. They do not want to be left behind “holding the inventory.” JIT leads to waste reduction improves productivity and (Kaswan S, et al. [4]) provides highquality patient care. The practical implementation of JIT depends on vital factors known as enablers. Grey Relational Analysis (GRA) has been used in the present study to rank enablers and ranks were further validated using the fuzzy technique for (Kaswan S, et al. [4]) order of preference by similarity to ideal solution (TOPSIS) and sensitivity analysis. Clinical nurse educators are expected to (White, et al. [5]) prepare students for the realities of practice while providing meaningful learning experiences.

However, shortened patient stays in the acute care setting often lead to wasted and useless effort for both instructors and students. The application of Just-in-Time principles offers a viable and alternative solution for clinical (White, et al. [5]) practice preparation in today’s rapidly changing healthcare environment. Different organization around the globe are using 5S (Ahsan Siddiqui [6]) and 7 Muda methodology to get benefits for improvement of their health care system. The step-by-step process of 5S and 7 Muda methodology is smart way to start monitor, finish and follow up the broken health system in several countries. Lean management and Lean six sigma methodology has shown promising results to improve the quality of health care system. Lean six sigma methodology works by reducing 8 wastes including overproduction, inventory, waiting, Motion, Transportation, rework, over processing and non-utilized talent. The 5 (Ahsan Siddiqui [6]) principles of lean model include value, value stream, flow, pull and perfection.

Healthcare providers are critical to disaster response (Ahsan Siddiqui [7]) throughout the world. Increasingly, there are government and nongovernment sponsored opportunities for providers to participate in disaster response as members of disaster response teams. Training opportunities on-line and in-person are readily available but not usually for a specific disaster at the time it occurs. Just-in-time disaster specific training prepares providers for imminent deployment for a real-time disaster. Particularly for disaster response (Ahsan Siddiqui [7]) in an austere environment just-in-time disaster specific training optimizes preparation and response.

Methods

The Author of this article has chosen the scoping review of the 37 articles and the websites to discuss details about the Just in time methodology. Scoping review focuses more on to discuss the 10 benefits/advantages of the JIT methodology and the 10 steps to perform JIT methodology. The author has chosen subject and words to find out the which organization should use the JIT methodology and some of the disadvantages of the JIT methodology. Articles are specially selected from the PubMed NIH website focusing only on healthcare JIT methodology. Just-in-time (JIT) has been a popular operation strategy partly (Ahsan Siddiqui [8]) because of its success in the Japanese automobile industry. Various benefits such as inventory reduction improved operations efficiency and faster response have been studied widely in previous studies. Therefore, successful implementation of JIT is vital to many companies. The major contribution (Ahsan Siddiqui [8]) of this paper lies in the discussions of the successful factors as a practical guide to implement JIT systems.

As we enter a new era of technological capacity for (Inbal NS [9]) delivering Just-in-time adaptive intervention (JITAIs). It is critical that researchers develop sophisticated and nuanced health behavior theories capable of guiding the construction of such interventions. Despite the increasing use and appeal of JITAIs, a major gap exists between the growing (Inbal NS [9]) technological capabilities for delivering JITAIs and research on the development and evaluation of these interventions (Figure 2). During the current recession economy around the globe, (Ahsan Siddiqui [10]) it is wise to choose the quality tools such as KAIZEN for the growth of organizations. Toyota motors, BMW Germany, Ford motors USA, other companies are using the KAIZEN tool to organize their organization, reduce the waste and increase the profits.

Figure 2: Marketbusinessnews.com [33].

SWOT tool helps administration to simplify the challenges an organization is facing and would face in the future to write and implement the corrective actions for improvement. SWOT analysis also helps to identify the (Ahsan Siddiqui [10]) 7 Muda wastes of the organization to reduce the wastes to make the organization reliable productive and profitable. Canonical correlation analysis was used to test five hypotheses. (Sadao S, et al. [11]) The results indicated that

a) There was not a significant relationship between the use of JIT practices alone and manufacturing performance,
b) There was a very strong relationship between JIT practices and infrastructure practices
c) The combination of JIT management and infrastructure practice was related to manufacturing performance
d) Infrastructure by itself is sufficient to explain manufacturing performance and
e) Manufacturing performance was [11] related to competitive advantage. The worsening global economy following the burst [12] of the dotcom bubbles in 2001 the financial tsunami in 2008. And the incessant rise in customer demand for better services have all contributed to shrinking profit margins for businesses around the world. One successful solution has been the adoption of Just-in-Time manufacturing systems which involve many functional areas of a firm such as manufacturing, engineering, marketing, and purchasing among others.

Just-in-Time Logistics extends the JIT concept in manufacturing to business logistics an area (Kee h, et al. [13]) that has been observed to account for more than 30 per cent of sales revenue for some firms. The price of alirocumab would have to be reduced (Dhruv S, et al. [14]) considerably to be cost-effective. Because substantial reductions already have occurred, we believe that timely independent cost effectiveness analyses can inform clinical and policy discussions of new drugs as they enter the market. Compared with a statin alone the addition of alirocumab cost $308 000 (UI, $197 000 to $678 000) per QALY. Compared with the combination of statin and ezetimibe replacing ezetimibe with alirocumab cost $997 000 (UI, $254 000 to dominated) per QALY. (Dhruv S, et al [14]) Incremental cost effectiveness ratio in 2018 U.S. dollars per quality-adjusted life-year (QALY) gained. JIT is a philosophy that can be applied to inventory (Kinney Bill C, et al. [15]) management operations to reduce waste achieve cost savings maximize space and improve quality of care. In the healthcare environment a prime vendor program is essential to a successful JIT program.

With the advent of a prime vendor program at Naval Hospital, Oakland, the advantages offered by JIT become available. JIT is an innovative approach to inventory management that has been successfully applied in the healthcare industry. The authors examine JIT and how (Bill C, et al [15]) this philosophy can further the goals of the prime vendor program and increase quality of care (Figure 3) (Tables 1-4).

Figure 3: SPSS diagram shows 30 websites & journal articles discusses about 10 principles (steps) of jit- just in time and agrees to the following 10 points: CIPS.org [34].

Table 1: 30 Websites & Journal Articles Discusses About 10 Principles (Steps) Of Jit- Just in Time and Agrees to The Following 10 Points CIPS.org [34].

Table 2: 30 Websites & Journal Articles Discusses About 10 Advantages of Jit- Just in Time And Agrees To The Following 10 Points: (Valleybox.com 2021).

Table 3: 30 Websites & Journal Articles Discusses About Who Should Use Jit – Just in Time and Agrees To The Following 06 Points: (Bluecart.com 2021).

Table 4: 30 Websites & Journal Articles Discusses About 06 Disadvantages of Jit- Just in Time and Agrees to The Following 06 Points (Netsuite.com 2021).

Results

There are four tables providing details about the 10 steps of the JIT methodology and its benefits/advantages. Remaining two tables provide the details about who should use the JIT methodology and its disadvantages. Author has provided the data analysis and diagrammatic presentation by using SPSS software. Four diagrams show the bar charts and the frequencies of the 30 articles of the steps, advantages, disadvantages and who should use the JIT methodology. Just-in-time (JIT) a management concept which requires (Whitson Daniel [16]) the delivery of a service or a product only upon demand can be used by hospitals as a tool for minimizing expenditures in logistics. This system offers a variety of benefits such as continuity in process flows minimization of works-in- process and finished goods inventory and the removal of bottlenecks in the production line.

Some of the areas wherein the JIT system (Whitson Daniel [16]) can be applied include central supply materials management and pharmacy nursing units and physician practices. During the time of recession and economic instability (Ahsan AS [17]) most of the organizations are looking to save money. The seven quality tools and other 29 administrative quality tools help the organizations to identify the problem, its root cause analysis and implement the corrective action to obtain the best possible result. By the literature review of the PESTEL/PESTLE analysis tool it helps the organization to focus on 6 important factors to grow the business. 6 important factors include political focus on health care, (Ahsan AS [18]) economic challenges, social factors, technological factors, legal factors, and the environmental factors. The present work provides important difficult and easy (Kaswan MS, et al. [19]) to implement JIT elements in healthcare services.

Besides this work justifies the application of decision-making tool (AHP, BWM) for the prioritization of JIT elements in the health care sector. This work also facilitates the proper management of inventory items together with the reduction in various Lean wastes with the proper implementation (Kaswan MS, et al. [19]) of JIT in healthcare. The reduction in various associated wastes leads to cleaner surrounding and lesser environmental degradation. This study examines the transformation of manufacturing industry (Krishnamurthy A [20]) to Just in Time (JIT) manufacturing and mass customization. The main objective is to identify strategies that will accelerate the realization of information technology enabled on demand services. Manufacturing and service systems are compared in terms of the similarities and differences with respect to issues related to their design planning and performance evaluation. These comparisons show that problems related to portfolio optimization workforce optimization and resources allocation are important in both manufacturing and (Krishnamurthy A [20]) service systems suggesting that the similarities be exploited to develop strategies for on demand services.

A new form of relational exchange commonly referred (Gary LF, et al. [21]) to as the “just-in-time” (JIT) exchange relationship has been adopted and implemented by many original equipment manufacturers (OEMs) and suppliers of component parts-materials during the past several years. The authors attempt to expand understanding of

a) How JIT exchanges compare with other forms of exchange between suppliers of component parts-materials and OEMs,
b) What conditions are most conducive to the initiation of JIT exchanges and
c) What key factors (Gary LF, et al. [21]) are likely to influence the success or failure of initiated JIT exchanges. We conclude that in a hospital with a sophisticated material (Epstein R, et al. [22]) management information system OR managers will probably achieve greater cost reductions from focusing on negotiating less expensive purchase prices for items than on trying to link the OR information system with the hospital’s material management information system to achieve just-intime inventory control.
Because expensive items typically have different models and sizes each of which is used by a hospital less often than this for almost all items there will be (Epstein R, et al. [22]) no benefit to making daily adjustments to the order volume based on booked cases. There are two keys to JIT supplier logistics that is taking control (Harry G [23]) of inbound deliveries and establishing quick feed-back loops. Various models have been proposed to investigate the improvement and learning processes the JIT system seeks to foster. To maximize the probability of success of a JIT program it is also necessary to put proper incentive systems in place that encourage employees and management to implement the desired changes and to redefine areas of responsibility throughout the organization. The extension of JIT across firms thus creates (Harry G [23]) mutual dependencies between supplier and customer and hence incentives to cooperate to resolve problems and increase efficiency (Figures 4-6).

Figure 4: SPSS Diagram Shows 30 Websites & Journal Articles Discusses About 10 Advantages of Jit- Just In Time And Agrees To The Following 10 Points: Valleybox.com [35].

Figure 5: SPSS Diagram Shows 30 Websites & Journal Articles Discusses About Who Should Use Jit – Just In Time And Agrees To The Following 06 Points: (Bluecart.com, 2021).

Figure 6: (Netsuite.com 2021).

Discussion

The analysis was conducted in a systematic manner and (Gary Jarrett [24]) compared the anticipated benefits with benefits validated in other industries from the implementation of JIT. In this particular study the cost and benefit outcomes achieved from a health care JIT implementation were compared with those achieved by the manufacturing service and retail industries. Chiefly, it was found that the health service market must be restructured to encourage greater price competition among priorities. A new standardization process (Gary Jarrett [24]) should eliminate duplication of products and realize substantial savings. Nurse executives need to review what is working in (Jacobs SM, et al. [25]) other industries to see if similar techniques and philosophies can help the healthcare industry. The authors review the manufacturing philosophy supporting the just-in-time JIT method and apply some of its (Jacobs SM, et al. [25]) principles to healthcare to improve operations and operating margins.

Describes one approach to meeting the health‐care cost reduction (Heinbuch SE [26]) challenge through the hospital materials management function. Highlights the value of taking a proactive stance to meet the challenge, transferring technology across industry sectors such as employing a just‐in‐time inventory management system in clinical areas of hospital materials (Heinbuch SE [26]) management and adopting a win‐win managerial philosophy. Features a case study to demonstrate the ideas in practice. With the implementation of the recent Healthcare Reform Act (Bhushan K [27]) and the increased scrutiny on the soaring costs of healthcare medical plans are looking for ways to optimize workflows and reduce costs. Titan Healthcare is a large non-profit integrated healthcare company located in Arizona New Mexico, Nevada, Colorado, and Texas. They provide health insurance coverage and a broad range of comprehensive health care.

From a pharmacy inventory (Bhushan K [27]) perspective expectation for the system is to significantly reduce inventory costs and increase service levels to their members. With the recent public focus on health care reform hospitals (Yitteck Walker [28]) are under more pressure than ever to be more cost efficient. In order to accomplish these hospitals must explore new business models that will help them reduce costs while at the same time increasing productivity. The just-in-time (JIT) inventory system is selected in this project as a potential cost saving strategy for hospitals. This project explores the feasibility of adopting a JIT inventory system (Yitteck Walker [28]) in a hospital setting through a detailed review and comparison of 20 articles. Lean management aims to add value to the patient (Tomasz K [29]) and the healthcare unit by eliminating superfluous and non-value adding activities. The purpose of the article is to discuss the implementation of lean management/lean healthcare solutions to the healthcare units thanks to the use of a value-adding Just-in-Time (JIT) method in hospital inventory management. The article is based on [29-39] an up-to-date subject literature and was conducted by means of desk research analysis.

Conclusion

To conclude, just in time methodology (JIT) is a lean methodology to provide economic comfort to the organization. JIT has proven that it could save lot of wastes for the organization and provided affective savings for the organization. The method to get the benefit is to order only what is needed and do not waste the time and money in inventory stocks. Toyota motors, Apple, McDonald and others are successful organizations taking huge benefits from the JIT methodology from decades. Small businesses should practice JIT methodology, which is convenient to use and sensible, easy to implement in the organizations.

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Impact of Automaticity Skills on Students’ Success in O-Chem I

Opinion

The Texas Networking for Science Advancement (NSA) team previously reported in this journal on how student’s automaticity ability (what can be done without the use of a calculator) influences their success in general chemistry [1,2]. The published general chemistry statistics for the MUST (Math-Up Skills Test) consistently support that this assessment is highly reliable (KR-20 > .80), has good internal consistency (Cronbach’s alpha > .85), and the Cohen’s d for the MUST is consistently > 1.0 indicating a large effect size for a population of over 10,000 [2]. Given these statistics, the NSA team turned its attention to how do automaticity skills assessed by the MUST reflect students’ success in first-semester organic chemistry (O-Chem I), a course commonly referred to as the “pre-med killer” or the hardest pre-med course. If you ask a student who has taken organic chemistry what they recalled most about the course, there is a slim chance you would hear them reference mathematics. However, mathematics does exist in O-Chem in forms that reflect lessons from the foundation courses that students have taken and passed, like general chemistry and calculus. Some example lessons in O-Chem that need calculations include:

 Drawn chemical structures/empirical formulas and calculating the molecular weight

 PH determination

 Enthalpy and entropy to determine endothermic/exothermic reaction conditions

 Bond dissociation energies of molecules

 Kinetics and rate equations

 Energy of activation with the Arrhenius equation

 Percent yield, weight/weight%, volume/volume%

 Conversions factors (mole to mmol) or concentrations

 J-splitting in nuclear magnetic resonance (NMR) spectra

 Molar extinction coefficient (Ɛ) from Beer-Lambert equation in UV-Vis

 Change in wavelength in infrared spectroscopy bands when groups shift positions

Knowing that MUST skills are linked to success in general chemistry, led the NSA team to investigate how students’ arithmeticautomaticity ability might lead to a better understanding of whom will succeed in O-Chem I. In this study, the MUST was given to O-Chem I students (n = 99, no incompletes or withdrawals were considered in the analysis) at the beginning of a semester at two Texas universities, one public Hispanic Serving Institution (HSI) and one private Hispanic-emerging institution. The MUST scores were then matched to the respective students’ final course grades and compared. A copy of the 12 min, 20-question MUST is available in Williamson, et al. [3]. Surprising was that these results continued to mimic those of general chemistry students (Figure 1). The left side of Figure 1 depicts three groups (I – III) of students. The MUST mean and SD are 9.99 (5.50). Group I students (bottom, blue group) are those who scored above average (> 13 of 20 questions) on the MUST. Students in group II (middle, orange group) are those who scored in the average group range (7-13 correct questions), and group III (top, green group) consists of students who scored < 7 correct. On the right side of (Figure 1), the two groups U and S reflect those who completed O-Chem I successfully (grades of A, B, or C) and those who did not attain at least a grade of C or a numerical average of > 69.5%. We did not hypothesize that there would be any relationship between students’ MUST scores and their success in O-Chem I, but as can be seen, almost all group I students were successful in O-Chem I as were most of the students in the average group.

Figure 1: Alluvial diagram comparing MUST scores to completion level of O-Chem I students. Left vertical bar identifies three MUST groups (I = above average scores, II = average scores, and III = below average scores). Right vertical bar identifies two student groups (U = unsuccessful and S = successful). Alluvial diagram source: https://rawgraphs.io/learning/how-to-makean- alluvial-diagram/#01-paste-your-data.

About half of group III students (identified the first week of class!) failed to successfully complete O-Chem I and are therefore not allowed to progress to O-Chem II and probably have a slim chance of continuing the pre-med track. Mathematics and underlying thought processes are prevalent in some form in most chemistry courses, including organic chemistry. Success on the MUST goes beyond basic arithmetic understanding and reflects what students have “overlearned.” Processing an ability to retain certain facts in long-term memory provides an edge to succeed in O-Chem I. It is students’ prior knowledge that continues to be the most predictive factor of determining success in the next course. The knowledge a student brings to the next course is always confronted with new applications that must be incorporated into their chemical repertoire, but as has again been shown, the more arithmetic facts that can be correctly recalled without the use of a calculating device, the more successful on the average students will be. The MUST is a fast, simple assessment of students’ arithmeticautomaticity ability that can be used to determine those who are predicted to struggle in only 12 min. the first day of class.

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Successful Desensitization to Dacarbazine Using Pretreatment with Omalizumab

Introduction

Dacarbazine (DTIC) is an antineoplastic drug that belongs to the group of the alkylating agents (they destroy cells by attaching an alkyl group (CnH2n+1) to their DNA) (Table 1). It is used to treat several cancer types (i.e., melanoma, Hodgkin lymphoma, pancreatic islets carcinoma and some types of sarcoma). It is often administered in combination chemotherapy, for example in the ABVD regimen used in the first-line treatment of Hodgkin lymphoma, in which A stands for Adriamicine, B for Bleomicine, V for Vinblastine and D for Dacarbazine. Dacarbazine-induced adverse drug reactions (ADR) can be caused by several mechanisms, i.e., drug interactions when it is given simultaneously to other drugs that are metabolized through the cytochrome P450 -this liver enzyme is needed for the activation of dacarbazine by demethylation. Hypersensitivity reactions seem to be infrequent when we look at the scarce number of published papers regarding this subject. Different types of reactions have been described, both immediate (anaphylactic shock, urticaria) and delayed (hypersensitivity syndrome, allergic hepatotoxicity, photosensitivity -phototoxic dermatitis-, fixed drug eruption, eosinophilia) [1-5].
Even if an IgE-mediated mechanism has not been established, the clinical picture of some of the immediate reactions in which dacarbazine is involved suggests that they could be caused by this immunological mechanism. We must take into account that the dacarbazine formulation available in Spain contains mannitol as an excipient, which could have a role in causing some of the dacarbazine-induced ADR, acting as an allergen itself or by means of a non-immunological mechanism (for example, inducing histamine release when it is given intravenously as hyperosmolar solutions) [6-8].

Table 1: Classification of alkylating agents.

Case Report

We report the case of a 19-year-old man diagnosed with Hodgkin’s disease who presented an immediate reaction after receiving treatment with doxorubicin (adriamicine), bleomycin, vinblastine and dacarbazine. He had an atopic background: he had previous diagnosis of chlorhexidine allergy (generalized urticaria after its topical use), atopic dermatitis in childhood, kiwi allergy (oral allergy syndrome) and allergic rhinitis with grass pollen and cat sensitivity. The reaction during the administration of chemotherapy started with an itchy feeling of his throat and the base of the tongue that progressed to respiratory distress, generalized urticaria and facial angioedema. The symptoms resolved within an hour after he was given 100 mg of hydrocortisone. It was the first time that he received this treatment. Skin prick tests with doxorubicin, bleomycin, vinblastine and dacarbazine were empirically performed (Table 2); we obtained a doubtful positive result with dacarbazine. We did not perform intradermal tests because of the vesicant effect that has been described with some of these drugs (doxorubicin, vinblastine) and also because we didn´t find published concentrations for such tests with these drugs.

Table 2: Prick concentrations.

Given the results of the tests and the signs and symptoms presented by the patient, a 19 step, 4 concentrations (Table 3), desensitization protocol was performed in the Intensive Care Unit (ICU) of our hospital. The patient was given premedication with 8 mg of dexamethasone, dexchlorpheniramine and ondansetron. During the infusion of the last bag, he complained of pruritus in the base of his tongue and dyspnea. He was treated with dexchlorpheniramine and 100 mg of hydrocortisone, and the infusion was continued at a 30 ml/h speed. At that moment, he developed a systemic urticaria. It resolved with a new dose of dexchlorpheniramine and 100 mg of hydrocortisone. We stopped the procedure; so we couldn’t achieve the desired the full dose. The next desensitization procedure was also performed at the ICU; this time the patient was premedicated with a single dose of 300 mg of Omalizumab, given three weeks before the desensitization. The patient took at home acetylsalicylic acid 300 mg, montelukast 10 mg, prednisone 30 mg and cetirizine 10 mg the previous two days to the desensitization day, and acetylsalicylic acid 300 mg and montelukast 10 mg on the third day.

Table 3: first desensitization with dacarbazine protocol.

Note: Dilution 1: 0,0028 mg/ml (0,14 mg/50 ml)
Dilution 2: 0,0284 mg/ml (1,42 mg/50 ml)
Dilution 3: 0,2844 mg/ml (28,44 mg/100 ml)
Dilution 4: 1,4108 mg/ml (705,39 mg/500 ml)

Blood samples were obtained before the procedure in order to get basal values of tryptase and total IgE and the hospital premedication was modified; he was given intravenous dexchlorpheniramine, 50 mg of ranitidine, 8 mg of ondansetron and 16 mg of dexamethasone. A 3 bag, 13 step protocol was followed (Tables 4-6). About 90 minutes after the last infusion speed (120 ml/h) was started, he presented a few isolated, non-pruritic hives that were treated with intramuscular injection of 40 mg of methylprednisolone, without stopping the desensitization. New blood samples were drawn and dexchlorpheniramine was added; the procedure could be successfully finished. One hour after the desensitization had finished the skin lesions disappeared. Subsequent desensitizations were performed with the administration of omalizumab one week before each new treatment cycle (it was given every two weeks). The previously described 13 step regime was followed, although a new dose of dexchlorpheniramine was added before the change to the 120 ml/h infusion speed. Hitherto, he has tolerated all the desensitizations.

Table 4: Desensitization with dacarbazine protocol previous omalizumab treatment.

Table 5:

Note: (*) Before step 13 dexchlorpheniramine is given
Total duration of the procedure: 6h 51’

Table 6: Results of the blood work up of the 2nd desensitization.

Discussion

Previous desensitizations to dacarbazine have been described, but they represent a tiny part of the procedures that have been performed to other antineoplastic drugs; we haven’t found descriptions of skin testing with this drug [9,10]. As we don’t know which concentration of dacarbazine causes irritation during skin testing, we think that the drug concentration we used for the skin prick test (2 mg/ml) requires further validation, testing it in, ideally, at least 10 controls (which we didn´t perform). Patients who develop an allergy to dacarbazine could react to the administration of temozolomide, because of the similar molecular structure of these molecules (Figure 1). This could be troublesome for melanoma patients, because both drugs are therapeutic options in these patients. Anyway, it’s an unlikely event, because temozolomide is mainly used in cerebral tumors. Besides, even if cross reactivity between these two drugs was possible, their different route of administration (dacarbazine is given intravenously and temozolomide per os) may cause different clinical reactivity [5].

Figure 1: Chemical structures of some alkylating agents.

Both drugs, and also procarbazine, produce as intermediate agents alkyl diazonium derivatives, which are responsible of the alkylation of biologic molecules. It has yet to be stablished if these products can have a pathogenic role in the adverse reactions to these drugs. Our patient had a serious reaction during his first exposure to dacarbazine. The mechanism involved in the reaction could be immunological or non-immunological. If we consider a possible immunological mechanism, the previous sensitization could have happened by contact with molecules structurally similar to dacarbazine or by developing a sensitization to mannitol, the excipient used in the dacarbazine commercial formulation. Mannitol is a ubiquitous agent, often used in food and pharmaceutical industry. One of the main limitations of our study is that we didn’t perform skin tests with mannitol; the other, the fact that we didn´t test the concentrations we used for prick test in controls.
Considering the likelihood of an IgE-mediated mechanism in the dacarbazine-induced reaction, it would be necessary to have validated and reliable skin tests to obtain a diagnosis, especially in patients like ours who have their reaction in the context of the simultaneous administration of multiple antineoplastic drugs, thus making very challenging the identification of the culprit drug which will probably have to be readministered using a desensitization protocol. Also, knowing whether there is or there isn’t an immunological sensitization can help us stratify better the risk in order to choose the proper protocol in the desensitization [10,11]. As it has been described elsewhere, omalizumab is useful as an adjuvant therapy in the desensitizations that are unsuccessful with the standard protocols [12,13].

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