exploratory research and

EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE

CONTENTS 2017 2(2):33–46

Review Article

Neurally Adjusted Ventilatory Assist Mode in Pediatric Intensive Care Unit and Pediatric Cardiac Care UnitMonika Gupta, Maria Bergel, Nicole Betancourt, Vicki L. Mahan . . . . . . . . . . . . . . . . . . . . . 33

Original Article

Accuracy in the Division of Acetaminophen SuppositoriesCarlo Valerio Bellieni, Elena Dreassi, Sara Cornacchione, Monica Tei, Francesca Coccina, Giuseppe Buonocore . . 38

Case Report

Eosinophilic Esophagitis due to Gluten without Celiac Disease and Unusual ComorbiditiesGómez Torrijos Elisa, Yesica Mendez Diaz, Lucía Moreno Lozano, Alba M.Extremera Ortega, Joaquin Rodriguez Sanchez-Migallon, Jesus M.Borja Segade, José Fco Feo Brito, Rosa García Rodríguez . . . . . . . . . . . . . 41

Exploratory Research and Hypothesis in Medicine 2017 vol. 2 | 33–37

Copyright: © 2017 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 International License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Review Article

Introduction

Conventional modes of ventilation currently used in pediatric and cardiac intensive care units (PICUs and CICUs, respectively) in-clude volume, pressure or combination modes. These are mostly assist modes, as they are delivered by means of pneumatic sig-nals generated by patient effort. Though these currently serve the purpose of oxygenation and ventilation, these are not ideal due to asynchrony and effect on patient’s work of breathing.

Neurally adjusted ventilator assist (NAVA) mode was predomi-nantly developed by Sinderby et al. to promote comfort in neo-

nates.1–3 To understand this novel mode of ventilation, we must first understand the physiology of normal ventilation. A variety of signals constantly provide neural feedback via complex regula-tory systems, such as stretch receptors in the lungs, the Hering-Breuer reflex, lung compliance changes, upper airway receptors, peripheral and central chemoreceptors. These signals originate in the respiratory center of the brain stem and are then carried via the phrenic nerve to the diaphragm resulting in diaphragmatic con-traction and subsequent chest expansion. This process generates negative pressure in the thoracic cavity, drawing in air and causing expansion of the lungs and consequent changes in pulmonary pres-sure, flow and volume.1–4

NAVA utilizes electrical voltages travelling via the phrenic nerve (known as electrical activity of the diaphragm (Edi); Fig. 1) as a marker of respiratory effort in guiding the ventilator for initiation of respirations. A specialized nasogastric tube, with eight bipolar elec-trodes (sensors), is positioned in the lower esophagus at the level of the crural diaphragm to measure the Edi signal (Figs. 2–4).

As seen in Figure 1, in a healthy volunteer in the resting state, low Edi voltages can maximally recruit diaphragmatic muscles, generating a normal tidal volume (green diaphragm). However, when patients initially become sick (yellow diaphragm), higher Edi voltages are needed to achieve the same tidal volume. Sicker patients (red diaphragm) maximize Edi voltages from the neural center and are unable to generate adequate tidal volumes.

Edi signals

The Edi signal depends on nerve fiber recruitment (i.e. the number

Neurally Adjusted Ventilatory Assist Mode in Pediatric Intensive Care Unit and Pediatric Cardiac Care Unit

Monika Gupta1,2,3*, Maria Bergel1,3, Nicole Betancourt1,3 and Vicki L. Mahan1,2,4

1St Christopher’s Hospital for Children, Philadelphia, PA, USA; 2Drexel University College of Medicine, Philadelphia, PA, USA; 3Section of Critical Care Medicine, Department of Pediatrics, St Christopher’s Hospital for Children, Philadelphia, PA, USA; 4Section of Pediatric

Cardiothoracic Surgery, Department of Pediatric Surgery, St Christopher’s Hospital for Children, Philadelphia, PA, USA

Abstract

Neonatal, cardiac and pediatric intensive care units (ICUs) frequently use the neurally adjusted ventilatory assist (NAVA) mode of ventilation, which has been shown to improve patient-ventilator synchrony and decrease work of breathing as it uses neural impulse to guide patient and ventilator breaths. We reviewed uses of NAVA as the mode of ventilation and oxygenation in pediatric (P)ICU and cardiac (C)ICU patients. We found that NAVA mode improves patient-ventilator interaction by improving synchrony and thus decreasing work of breathing. This eventually im-proved all aspects of critical care, as demonstrated by decreased need for sedation, improvement in hemodynam-ics, improvement in patient comfort, decreased days on ventilator, decreased days in ICU and decreased hospital length of stay. Additional studies need to be done in order to help NAVA technology become a primary mode of ventilation in PICU and CICU. Further studies are also needed to evaluate the successful use of noninvasive-NAVA as a means of preventing endotracheal intubation or to allow early extubation in our population.

Keywords: Neural; Mechanical ventilation; Respiratory failure.Abbreviations: NAVA, neurally adjusted ventilatory assist; NIV-NAVA, non invasive neurally adjusted ventilatory assist; PICU, pediatric intensive care unit; CICU, cardi-ac intensive care unit; Edi, electrical activity of diaphragm; Edi-min, electrical activ-ity of diaphragm minimum; NEX, nose- ear- xiphoid; PEEP, Positive End-Expiratory Pressure; PIP, peak inspiratory pressure; EKG, electro-cardio-gram; µV, microvolts; PC, pressure control; PS, pressure support; PRVC, pressure regulated volume control; RSV, respiratory syncytial virus; COMFORT, comfort scale; CDH, congenital dia-phragmatic hernia; ARDS, acute respiratory distress syndrome; SIMV, synchronized intermittent mechanical ventilation; nCPAP, nasal continuous positive airway pres-sure; NIPPV, nasal intermittent positive pressure ventilation.Received: December 19, 2016; Revised: March 23, 2017; Accepted: April 18, 2017*Correspondence to: Monika Gupta, Drexel University College of Medicine and Dentistry, 160 East Erie Ave, Philadelphia, PA 19134-1095, USA. Tel: (215) 427 8812, Fax: (215) 427 5525, E-mail: [email protected]; [email protected] to cite this article: Gupta M, Bergel M, Betancourt N, Mahan VL. Neurally Ad-justed Ventilatory Assist Mode in Pediatric Intensive Care Unit and Pediatric Cardiac Care Unit. Exploratory Research and Hypothesis in Medicine 2017;2(2):33–37. doi: 10.14218/ERHM.2016.00027

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Gupta M. et al: Neurally adjusted ventilatory assist mode in PICUExplor Res Hypothesis Med

of neurons that are sending the stimulus) and patient’s respiratory rate. Signals from each electrode pair are differentially amplified, digitized and processed by specialized NAVA software. Electrical contamination from the heart, esophagus and environment are fil-tered and silenced to obtain the highest possible signal-to-noise ratio. In patients on NAVA, the following anatomic factors do not influence Edi signals: lung volume, body position, intra-abdominal pressure, postural and expiratory muscles, subcutaneous layers, applied positive end-expiratory pressure (PEEP), nasogastric feeds or milk influx during oral feeding.

Factors that decrease or alter Edi signals include failure to de-liver respiratory signals due to apnea of prematurity, central hy-poventilation syndrome, over-assist, hyperventilation, brain injury and sedation, as well as anatomic reasons (i.e. diaphragmatic her-nia) and peripheral abnormalities such as phrenic nerve conduction failure, disease, or chemical paralysis of the neuromuscular junc-tion or diaphragm.

Placement of the Edi catheter

Edi catheter placement, similar to nasogastric or oro-gastric tubes, uses measurements from nose to ear to xiphoid distance. The for-mula for insertion is included in the insert of the package from the manufacturer of the representative catheter shown in Figure 2 (Maquet, Rastatt, Germany).

As seen in Figure 5, correct catheter position is demonstrated by the presence of the largest p-waves in the upper leads and by QRS complexes in the middle leads. There is subsequent progression to minimal or absent p-waves and QRS complexes in the lower leads. The Edi signal is superimposed on the retro-cardiac electrocardio-gram as a lavender/purple color on the second and third lead.

The highest Edi value of the waveform (Edi peak) represents neural inspiratory effort and is responsible for the size and duration of the breath. The lowest Edi (Edi min) represents spontaneous tonic activity of the diaphragm, which prevents de-recruitment of alveoli during expiration. The Edi trigger (µV; the minimum in-crease in electrical activity from the previous trough) triggers the

Fig. 2. Insertion distance for nasogastric Edi Catheter. Abbreviations: Edi, Electrical activity of diaphragm; NEX, Nose- Ear- Xiphoid.

Fig. 3. Edi catheter in relation to diaphragm. 1. Edi catheter; 2. Esopha-gus; 3. Diaphragm; 4. Gastric mucosa. Abbreviation: Edi, Electrical activity of diaphragm.

Fig. 1. Edi signal in healthy vs. sick patients. Abbreviation: Edi, Electrical activity of diaphragm.

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Gupta M. et al: Neurally adjusted ventilatory assist mode in PICU Explor Res Hypothesis Med

ventilator to recognize the increase in electrical activity, thereby resulting in initiation of a breath.

The NAVA level (cmH2O/µV; a conversion factor) translates the Edi signal into proportional pressures. Edi is multiplied by the NAVA level to determine airway pressure delivered by the ventila-tor for each breath. The NAVA software automatically calculates peak inspiratory pressure (PIP) every 17 minutes. This is demon-strated by the formula

PIP = NAVA level × (Edi peak − Edi min) + PEEP.

Setting up NAVA as mode of ventilation

Setting up NAVA mode of ventilation involves the set-up of NAVA, NAVA pressure support (PS) mode and NAVA backup pressure control (PC) mode, enabling the patient to transition between all three modes. The ventilator has a preset apnea time default; how-ever, this can be altered based on the patient’s age and respira-tory rate. This ensures safety of patients should the Edi catheter disconnect or upon leakage of signals, absence of patient respira-tory effort or other reasons for asynchrony. Clinical comfort and blood gases are used to determine the appropriate level of support. Edi peak may be influenced by the amount of ventilatory support provided. Overventilation can suppress spontaneous respiratory drive and decrease the Edi signal. Underventilation can result in increased respiratory drive and higher Edi signals.1–4

Safety mechanisms for NAVA

In order to safely promote intermittent lung recruitment, the pa-tient’s ability to generate sufficient inspiratory pressure should be considered when setting a PIP limit. The PIP limit is set to prevent excessively large breaths; the ventilator will waste excessive tidal

volume at 5 cmH2O below the set PIP limit. A level that is set too low results in an inability to generate a sigh or recruiting breaths; this may result in the development of progressive atelectasis.

Should the Edi catheter become mal-positioned, dislodged, or fail to detect the Edi signal, the ventilator reverts to NAVA PS. In a clinically apneic patient, the ventilator switches to NAVA PC. Upon Edi signal return, NAVA reverts to previous settings.

The ventilator delivers inspiratory pressure only as long as the Edi signal is detected. At the point of optimal lung inflation, the Hering-Breuer reflex is stimulated. This stretch reflex functions as a negative feedback mechanism to terminate the Edi signal and ar-rest ventilator flow, protecting the lung from overinflation.

Use of NAVA mode of ventilation in PICU and CICU patients

Optimization of assist-ventilation with NAVA, without the delays seen in conventional ventilation, has been proven over multiple cross-over studies in the pediatric and infant population, as well as in at least one parallel pilot study.5 Invariably, these studies have shown a decrease in asynchrony in the infant and pediatric popula-tions when compared to both PC and PS conventional ventilation. Similar results were shown in a 10-patient infant study by Bordes-soule et al. in 2012.6 The authors demonstrated statistically signifi-cant decreases in trigger delay, asynchrony index, wasted effort and an increased correlation between the ventilator and Edi. A separate study demonstrated an asynchrony index of 0% in 14 preterm neo-nates over the course of 12 hours of NAVA ventilation as compared to 22% in neonates ventilated in pressure regulated volume con-trol (PRVC) mode.7 Investigators have also demonstrated a total of 1,841 neural apneas during PRVC ventilation, with a median dura-tion of 29 seconds; patients receiving NAVA ventilation had no neu-ral apneas. This was hypothesized to be related to overventilation and support while in the PRVC mode.7 In another study by Liet et al., the use of NAVA in children admitted with respiratory distress secondary to respiratory syncytial virus bronchiolitis was found to be effective because of its ability to minimize asynchrony.8 Based on findings of improved oxygenation and lower inspiratory pres-sures, the authors hypothesized that synchrony improves assist de-livery, prevents air swallowing and gastric distention, and improves pulmonary gas exchange, systemic blood flow and oxygen supply to tissues, decreasing morbidity, duration of ventilation and hospital length of stay.8 Additionally, Piastra and colleagues showed signifi-cant decreases in PIP, overall decrease in mean airway pressure and heart rate.5 The authors also demonstrated improved COMFORT score in patients under 1 year of age who were weaned from high frequency oscillatory ventilation to extubation via NAVA, as op-posed to pressure supported ventilation.5

In patients with acute respiratory distress syndrome (ARDS), NAVA could potentially be associated with significant physiologi-cal advantages over conventional ventilation. ARDS results in var-iable breathing patterns that affect metabolic demands, acid-base status and respiratory system mechanical properties. The prelimi-nary physiological findings obtained by a small study conducted by Terzi et al. suggest that neural triggering provides a more ef-fective means of weaning mechanical ventilation in patients with ARDS, while minimizing the hazards of dynamic hyperinflation.9 The aforementioned 10-patient study of infants <1 year of age also demonstrated improved breath-to-breath variability with NAVA, providing corresponding variable pressure delivery in comparison to PC and PS ventilation.6

The successful use of NAVA in a patient with congenital dia-phragmatic hernia (CDH) pre- and post-repair has also been de-

Fig. 4. Measurement for Edi catheter placement. 1: Nose, 2: Ear, 3: Xi-phoid process. Abbreviation: Edi, Electrical activity of diaphragm.


Gupta M. et al: Neurally adjusted ventilatory assist mode in PICUExplor Res Hypothesis Med

scribed in a single case report.10 In this case, NAVA was imple-mented after synchronized intermittent mechanical ventilation PC/PS failed within 24 hours of intubation secondary to asynchrony and discomfort. Upon switching to NAVA, the patient appeared more comfortable, resulting in sedation wean. Minehart et al. dem-onstrated that despite a defect in the diaphragm, Edi signals allowed for synchronized ventilation pre- and post-operatively. The child was extubated on postoperative day 1.10 Of note, there are addi-tional case reports on the use of NAVA in patients post-CDH repair.

Data is very limited regarding use of NAVA in postoperative congenital cardiac patients. In 21 postoperative cardiac patients, Bengtsson et al. demonstrated safe and potentially efficacious use of NAVA, improvement in patient-ventilator synchrony, reduction in airway pressures and trends towards early extubation.11 In another study, Zhu and colleagues compared hemodynamic safety, oxygena-tion and gas exchange effects on patients with NAVA and pressure

ventilation. They confirmed that there is no effect on hemodynamics in most of the postoperative cardiac patients.12 Additionally, they found that the P/F ratio in the NAVA group was slightly higher than conventionally ventilated patients.12 More studies are needed in this area to help bring this technology into mainstream practice.

Future research directions

The majority of literature on the clinical use of NAVA is based on its use in intubated patients. However, there are studies that dem-onstrate the successful use of noninvasive NAVA (NIV-NAVA) in neonates. Firestone et al. evaluated PIPs and Edi in premature in-fants using NIV-NAVA respiratory support.13 In a study by Long-hini et al. comparing the use of NAVA before and after extubation, there was no difference found in patient-ventilator interaction, gas

Fig. 5. Display on ventilator confirming appropriate placement of Edi catheter. Abbreviation: Edi, Electrical activity of diaphragm.


Gupta M. et al: Neurally adjusted ventilatory assist mode in PICU Explor Res Hypothesis Med

exchange, sedation requirements or vital signs between invasive and NIV-NAVA.14 There is, however, a trend in pediatric critical care towards the use of nasal continuous positive airway pressure or nasal intermittent positive pressure ventilation in order to poten-tially prevent intubation and to support the patient’s cardiorespira-tory status post-extubation. Therefore, there is a probable role for the use of NIV ventilation with NAVA, particularly in neonates and infants in our PICU.

As we have seen in our PICU, the infants receiving NIV ven-tilation for acute respiratory failure often fail to synchronize with the ventilator, resulting in inefficient ventilation and oxygenation. Asynchrony during ventilation can have numerous adverse effects on the infant, namely increased mean airway pressure, fraction of inspired oxygen requirements, risk of barotrauma, risk and compli-cations of sedation and risk of hemodynamic instability.13 The use of NIV-NAVA in our neonate and infant populations could provide more effective synchronized ventilation that is more comfortable and less harmful and could also potentially lead to successful early extubation and decrease need for re-intubation. Additional studies need to be done in order to evaluate the successful use of NIV-NAVA as a means of preventing endotracheal intubation or to al-low early extubation in our population.

Limitations

While NAVA improves arterial oxygenation and alveolar venti-lation in pediatric patients by way of comfortable, synchronous ventilation with lower peak airway pressures, there are some sig-nificant drawbacks to this technology. NAVA is a new mode of ventilation, requiring some degree of adaptation and education in order to achieve the aforementioned benefits. Also, the Edi cath-eter is relatively expensive, although it does have the additional capability of use for feeding.9 The NAVA technology itself is also expensive, due to the need for specialized software on the ventila-tors and frequent changing of the Edi catheters.

Conclusions

NAVA ventilation is an innovative way of providing more ef-fective ventilation to intubated patients in the critical care set-ting using a sensitive physiologic trigger to initiate breaths. The comparative NAVA studies have demonstrated improved patient-ventilator synchrony with adequate oxygenation and ventilation. As the field of critical care (PICU and CICU) continues to favor less invasive interventions, there is much potential to use NIV-NAVA in order to prevent reintubation and facilitate successful early extubation.

Conflict of interest

The authors have no conflict of interests related to this publication.

Author contributions

Literature search (MG, MB, NB, VLM), writing sections of the manuscript and supervision (MG, VLM), writing pediatric cardiac care section of the manuscript (MB), writing pediatric intensive care section of the manuscript (NB).

References

[1] Maquet. Pocket Guide: NAVA® and NIV NAVA in neonatal settings. 2010.

[2] Courtesy of Stein H, Firestone K, Synderby C, Beck J. Materials from Workshop on NAVA. Toledo Ohio, Sept 2014.

[3] Stein H, Firestone K. Application of neurally adjusted ventilatory assist in neonates. Semin Fetal Neonatal Med 2014;19(1):60–69. doi:10.1016/j.siny.2013.09.005.

[4] Kacmarek RM. Proportional assist ventilation and neurally adjusted ventilatory assist. Respir Care 2011;56(2):140–148. doi:10.4187/respcare.01021.

[5] Piastra M, De Luca D, Costa R, Pizza A, De Sanctis R, Marzano L, et al. Neurally adjusted ventilatory assist vs pressure support ventilation in infants recovering from severe acute respiratory distress syndrome: nested study. J Crit Care 2014;29(2):312.e1–312.e5. doi:10.1016/j.jcrc.2013.08.006.

[6] Bordessoule A, Emeriaud G, Morneau S, Jouvet P, Beck J. Neurally adjusted ventilatory assist improves patient–ventilator interaction in infants as compared with conventional ventilation. Pediatr Res 2012;72(2):194–202. doi:10.1038/pr.2012.64.

[7] Longhini F, Ferrero F, De Luca D, Cosi G, Alemani M, Colombo D, et al. Neurally adjusted ventilatory assist in preterm neonates with acute respiratory failure. Neonatology 2015;107(1):60–67. doi:10.1159/ 000367886.

[8] Liet JM, Dejode JM, Joram N, Gaillard-Le Roux B, Bétrémieux P, Rozé JC. Respiratory support by neurally adjusted ventilatory assist (NAVA) in severe RSV-related bronchiolitis: a case series report. BMC Pediatr 2011;11:92. doi:10.1186/1471-2431-11-92.

[9] Terzi N, Pelieu I, Guittet L, Ramakers M, Seguin A, Daubin C, et al. Neurally adjusted ventilatory assist in patients recovering spontane-ous breathing after acute respiratory distress syndrome: physiologi-cal evaluation. Crit Care Med 2010;38(9):1830–1837. doi:10.1097/CCM.0b013e3181eb3c51.

[10] Tiffany M, Dixon C, Bozeman R, Patten W. Neurally adjusted venti-latory assist ventilation mode applied in congenital diaphragmatic hernia. Critical Care Medicine 2013;41(12):A297. doi:10.1097/01.ccm.0000440404.58412.fa.

[11] Bengtsson JA, Edberg KE. Neurally adjusted ventilatory assist in chil-dren: an observational study. Pediatr Crit Care Med 2010;11(2):253–257. doi:10.1097/PCC.0b013e3181b0655e.

[12] Zhu LM, Shi ZY, Ji G, Xu ZM, Zheng JH, Zhang HB, et al. Application of neurally adjusted ventilatory assist in infants who underwent cardiac surgery for congenital heart disease. Zhongguo Dang Dai Er Ke Za Zhi 2009;11(6):433–436.

[13] Firestone KS, Fisher S, Reddy S, White DB, Stein HM. Effect of chang-ing NAVA levels on peak inspiratory pressures and electrical activity of the diaphragm in premature neonates. J Perinatol 2015;35(8):612–616. doi:10.1038/jp.2015.14.

[14] Longhini F, Scarlino S, Gallina MR, Monzani A, De Franco S, Grassino EC, et al. Comparison of neurally adjusted ventilator assist in infants before and after extubation. Minerva Pediatr 2015.



Original Article

Introduction

Acetaminophen is the active metabolite of phenacetin, a weak in-hibitor of COX-1 and COX-2 in peripheral tissues, and does not have significant anti-inflammatory effects. Paracetamol has been used in clinical practice for over 100 years. Acetanilid, the parent compound of paracetamol, was introduced in 1886. However, tox-

icity-related problems with acetanilid lead to the introduction of paracetamol (acetaminophen, N- relationship between serum con-centration and acetyl-p-amino-phenol) by von Mering in 1893.1

Nowadays, acetaminophen is one of the most widely prescribed drugs in pediatrics, in which it is used to weaken fevers and attenu-ate pain2; its frequency of use is followed by ibuprofen. Acetami-nophen is well tolerated, lacks many of the side effects of aspirin, is available without prescription and is already widely used in the management of children with pain or fever.1

Current evidence suggests that there is no substantial difference in the safety and effectiveness of acetaminophen and ibuprofen in the care of a generally healthy child with fever. There is evidence, however, that combination of these two products is more effec-tive than their use as single agents. Yet, there are concerns that combined treatment may be more complicated and contribute to the unsafe use of these drugs. Pediatricians should promote patient safety by advocating for simplified formulations, dosing instruc-tions, and dosing devices.3

Accuracy in the Division of Acetaminophen Suppositories

Carlo Valerio Bellieni1*, Elena Dreassi2, Sara Cornacchione3, Monica Tei3, Francesca Coccina4 and Giuseppe Buonocore3

1Neonatal Intensive Care Unit, University Hospital, Siena, Italy; 2Department of Biotechnology and Chemistry and Pharmacy, University of Siena, Siena, Italy; 3Department of Pediatrics, University of Siena, Siena, Italy; 4Department of Pediatrics, University of Chieti,

Chieti, Italy

Abstract

Background and objective: Acetaminophen is the active metabolite of phenacetin, a weak inhibitor of COX-1 and COX-2 in peripheral tissues, and it is one of the most widely prescribed drugs in pediatrics, used to weaken fever and to attenuate pain. Different formulations and dosages are available on the market. Division of the suppository form is a widely-used technique and it allows for optimization of the dosage based on the weight of the child. Yet, few data are available in the literature about the effectiveness of this practice. The aim of this study was to evaluate the uniformity of distribution of acetaminophen inside the suppository and to verify the homogeneity of distribution after the division.

Methods: Two hundred and twenty-four suppositories of different batches, dosages and producers were exam-ined (Tachipirina®, Efferalgan®). One half of the suppositories (n=112) were divided by the same operator in two halves along the vertical axis, and the other half (n=112) were not divided but only weighed. In each of the groups (whole and fractional), the suppositories were evaluated by weight, acetaminophen content and the uniformity of the acetaminophen distribution.

Results: In no case did the partition of the suppositories led to significant differences (t-test) between weight of the head and tail portion. No significant differences in weight, acetaminophen content or acetaminophen distri-bution of the active component were present in any of the two halves of the total suppositories analyzed after the partition.

Conclusions: Splitting acetaminophen suppositories is a common practice and it is a convenient medical proce-dure, with low chance of error, and it should not raise concerns of accurate dosage.

Keywords: Acetaminophen; Suppository; Paracetamol.Abbreviations: COX, cyclooxygenase; AU, arbitrary unit; UV, ultraviolet.Received: February 28, 2017; Revised: May 25, 2017; Accepted: May 26, 2017*Correspondence to: Carlo Valerio Bellieni, Neonatal Intensive Care Unit, Univer-sity Hospital “Le Scotte” Siena, Viale M Bracci 8, 53100, Siena, Italy. Tel: 0039 0577 586550, Fax: 0039 0577 586182, E-mail: [email protected] to cite this article: Bellieni CV, Dreassi E, Cornacchione S, Tei M, Coccina F, Buonocore G. Accuracy in the Division of Acetaminophen Suppositories. Ex-ploratory Research and Hypothesis in Medicine 2017;2(2):38–40. doi: 10.14218/ERHM.2017.00003.



Bellieni CV. et al: Division of acetaminophen suppositories Explor Res Hypothesis Med

Many products containing acetaminophen, with different formu-lations and concentrations, are available on the market.4 In most cases, acetaminophen is administered orally, while rectal adminis-tration is used for the treatment of fever in vomiting patients or in circumstances where oral administration is otherwise not possible.2

A wide number of rectal drugs, with various dosages (125 mg, 150 mg, 250 mg, 300 mg, 500 mg, 1000 mg), are available on the market. The division of a rectal suppository is a widely-used tech-nique and it allows for optimization of dosage that is administered according to the weight of the child, but few data are present in the literature regarding the efficacy of such a practice.5

Study objective

The objectives of this study were to evaluate the uniformity of dis-tribution of acetaminophen inside suppositories of the investigated brands and to verify the homogeneity of distribution after the di-vision. In fact, positioning the suppositories in a steady position for long time during the production or the storage period might provoke an attraction toward the base of their components, due to gravity, which might differ for several reasons, such as viscosity or hydrosolubility.

Methods

Solvents and reagents

All solvents and reagents were from BHD (Poole, England). Stand-ard acetaminophen came from Sigma-Aldrich Srl (Milan, Italy). All commercial brand suppositories containing acetaminophen sold in Italy (125, 150, 250, 300 and 500 mg) were purchased in local drugstores.

Sample preparation

Two hundred and twenty-four suppositories of different batches, dosages and producers were examined (Tachipirina® Angelini, Ef-feralgan® Bristol Myers). One half (n=112) of the suppositories were divided by the same operator into two halves along the verti-cal axis; the two halves (head and tail) were then weighed. The

other half (n=112) of the suppositories were not divided, but only weighed.

Acetaminophen content was measured by UV-Vis spectroscopy. Each suppository, from both the whole or divided groups, were dissolved in a dichloromethane/isopropanol mixture (95:5 v/v) af-ter weighing. All samples were diluted with the same solvent mix-ture to have an UV absorption at 248 nm in the range 0.4–0.7 AU.

The partition of the suppositories was realized with the same technique that would be used in practice to yield one half the val-ue of the dose. The accuracy in partition was evaluated through comparison of the weight of the two portions of the suppositories (head and tail), its acetaminophen content and the uniformity of its distribution.

UV analysis

Suppositories (entire, head or tail) were dissolved and diluted by the aforementioned method, and the acetaminophen content was estimated through a calibration curve created on the basis of scalar solution in a dichloromethane/isopropanol mixture (95:5 v/v) in the range 0.002–0.025 mg/mL.

Results

The partition of the suppositories was simple to obtain, and the two portions (head and tail) retained their integrity so that they could be administered to a patient.

The results obtained for uniformity of weight of the various suppositories (entire, head and tail) are summarized in Figure 1. In no instance did the partition of the suppositories led to significant differences (t-test) between weights of the head and tail portions.

In view of the composition of all analyzed suppositories (aceta-minophen in synthetic triglycerides), the determination of the ac-tive component was carried out by UV spectroscopy, since the ex-cipients did not show significant absorption at the wavelength used (248 nm maximum absorption of acetaminophen in dichlorometh-ane/isopropanol solution). The results obtained for acetaminophen content in the various suppositories (entire suppository, head and tail) are summarized in Figure 2. All the suppositories analyzed (at least 10 samples from two production lots for each type) showed good uniformity of content (deviation from the theoretical value in the range ± 10%). In no instance did the partition led to significant

Fig. 1. Results for mean weigh ± standard deviation of suppositories, including entire suppositories and those partitioned into head and tail portions.

Fig. 2. Results for mean acetaminophen content ± standard deviation of suppositories, including entire suppositories and those partitioned into head and tail portions.


Bellieni CV. et al: Division of acetaminophen suppositoriesExplor Res Hypothesis Med

differences (t-test) between acetaminophen content of the head and tail portions.

The distribution of acetaminophen in the suppositories was de-termined with consideration to the weight of the sample (entire, head or tail portion), and the results are summarized in Figure 3. All the suppositories analyzed, of each brand investigated, showed a good homogeneity. In no case did the partition led to significant differences (t-test) between acetaminophen distribution of the head and tail portions.

Discussion

Partitioning acetaminophen suppositories is a common practice, but there are few data in the literature regarding the correctness and appropriateness of this kind of procedure.

Our study has shown that partitioning suppositories can be ef-fective, guaranteeing the desired dose, since both halves retain their integrity, so that they can be safely administered to patients; in fact, no significant differences in weight, acetaminophen con-tent and acetaminophen distribution were present in the two halves of the suppositories tested after splitting.

Our results are coherent with those of other studies which con-cluded that the analyzed commercial suppositories containing acetaminophen are of good quality in regard to homogeneity of content of the active ingredient. However, those authors concluded that the accuracy of partitions is unsatisfactory for achieving the target dose, and that only the whole suppositories were certain to contain the target dose.5

In our investigations, partitioning of the suppositories gave bet-ter results, with only 3 portions out of 328 (1 head and 2 tails) show-ing deviations from the target dose by more than 10% (+32.77%, −27.91% and −19.26% of the target dose, respectively). This study was limited, however, in its ability to establish if this deviation is

due to human error during the suppository portioning or if it is a product deviation.

Future research directions

Splitting suppositories is a viable medical procedure, since chance of error is very low and very much operator-related. Considering the homogeneous distribution of the drug inside the suppositories, each portion contains proportionally the right amount of active in-gredient.

The problem of dividing a tablet or a suppository accurately is not limited to acetaminophen, but involves other drugs, in particu-lar in pediatrics. A tight collaboration between pharmacologists and pediatricians is required, because when using drugs for infants or children that are otherwise formulated for adults it may become necessary to divide them, and it is indispensable to be aware of doing the right thing.

Conclusions

A manual split of a paracetamol suppository can be accurate and safe enough to be performed routinarely.




Performing the analysis of the suppositories (ED); coordinating the study (CVB); collecting the literature and writing the paper (SC, MT, FC); revising the study (GB).

References

[1] Anderson BJ. What we don’t know about paracetamol in chil-dren. Paediatr Anaesth 1998;8(6):451–460. doi:10.1046/j.1460-9592.1998.00295.x.

[2] Ohlsson A, Shah PS. Paracetamol (acetaminophen) for prevention or treatment of pain in newborns. Cochrane Database Syst Rev 2016;10:CD011219. doi:10.1002/14651858.CD011219.pub3.

[3] Section on Clinical Pharmacology, Therapeutics, Committee on Drugs, Sullivan JE, Farrar HC. Fever and antipyretic use in children. Pediatrics 2011;127(3):580–587. doi:10.1542/peds.2010-3852.

[4] Paracetamol. Available from: https://www.drugs.com/ingredient/acetaminophen.html.

[5] Szostak R, Mazurek S. Quantification of active ingredients in supposi-tories by FT-Raman spectroscopy. Drug Test Anal 2013;5(2):126–129. doi:10.1002/dta.379.

Fig. 3. Results for mean acetaminophen distribution ± standard deviation of suppositories, including entire suppositories and those partitioned into head and tail portions.

https://www.drugs.com/ingredient/acetaminophen.html

https://www.drugs.com/ingredient/acetaminophen.html



Case Report

Eosinophilic Esophagitis due to Gluten without Celiac Disease and Unusual Comorbidities

Gómez Torrijos Elisa1*, Yesica Mendez Diaz1, Lucía Moreno Lozano1, Alba M.Extremera Ortega1, Joaquin Rodriguez Sanchez-Migallon2, Jesus M.Borja Segade2,

José Fco Feo Brito1 and Rosa García Rodríguez1

1Allergology Service, Hospital General Universitario de Ciudad Real, Spain; 2Gastroenteriology Service, Hospital General Universitario de Ciudad Real, Spain

Abstract

In recent years, it has become recognized that patients with eosinophilic esophagitis (EoE) have an increased risk of multiple autoimmune diseases. Possible shared genetic aetiologies have been observed between EoE and au-toimmune diseases. Currently, it is believed that EoE is not associated with a higher risk of neoplasms since such published cases are very rare and there are only isolated reports. Herein, we describe a unique case of EoE due to gluten without coeliac disease. The patient presented some unusual comorbidities, such as hypothyroidism (autoimmune disease) and essential thrombocythemia (neoplasm of haematologic origin).

Keywords: Eosinophilic esophagitis; Gluten; Essential thrombocythemia; Autoim-mune disease; Dysfagia.Abbreviations: 6FED, Six-food elimination diet; EoE, Eosinophilic esophagitis; Eos/cga, eosinophils/high power field.Received: October 4, 2016; Revised: May 25, 2017; Accepted: May 26, 2017*Correspondence to: Elisa Gomez Torrijos, Hospital General Universitario de Ciudad Real. C/ Obispo Rafael Torija s/n. 13005 Ciudad Real, Spain. Tel: 0034 626356825, 0034 926278000, ext 79556, E-mail: [email protected] to cite this article: Elisa GóT, Diaz YM, Lozano LíM, Ortega AME, Sanchez-Migallon JR, Segade JMB, Brito JéFF, Rodríguez RGí. Eosinophilic Esophagitis due to Gluten without Celiac Disease and Unusual Comorbidities. Exploratory Re-search and Hypothesis in Medicine 2017;2(2):41–42. doi: 10.14218/ERHM.2016. 00011.

Introduction

Polycythemia vera, essential thrombocythemia and myelofibrosis are clonal disorders collectively identified as myeloproliferative neoplasms. The incidence and prevalence rates of myeloprolif-erative neoplasms, in general, have increased in the last decade,1 as has eosinophilic esophagitis (EoE).2,3 Moreover, studies of pa-tients with EoE have uncovered an increased risk of multiple au-toimmune diseases among this population. Possible shared genetic aetiologies have been observed between EoE and autoimmune dis-eases. Currently, however, it is believed that EoE is not associated with a higher risk of neoplasms, and this is primarily based on the fact that such published cases are very rare and there are only iso-lated reports in the medical literature.4

Case report

We report here the case of a 52-year-old male patient with a per-sonal history of non-allergic bronchial asthma. He reported having

experienced dysphagia with solid foods over the previous 9 years and isolated episodes of food impaction, which resolved spontane-ously.

An esophagogastroduodenoscopy with biopsies was performed, and samples were obtained from each targeted organ and from the three sections of the oesophagus. More than 30 eosinophils/high power field (eos/hpf) were found in the upper, middle and lower oesophagus, but no eosinophils were detected in the stomach or duodenum. No atrophy of intestinal villi was observed in the duo-denum.

After being treated with omeprazole (40 mgs bid) for 2 months, a new oesophagoscopy was performed with biopsies using sec-tions that detected >20 eos/hpf in the three oesophageal sections analysed.

Skin prick tests and specific IgE tests for wheat, milk, egg, lentils, peanuts, hake and shrimp were all negative. The patient was therefore diagnosed with EoE and subsequently treated with a food elimination diet. We instructed the patient how to follow the six-food elimination diet (6FED) with slight modification: we removed all cereals (with and without gluten) for 6 weeks. After the diet, the EoE remitted (0 eos/hpf in the oesophageal biopsies).5 The eliminated foods were then introduced sequentially (one-by-one), with biopsies performed at 6 weeks after the introduction of each food in order to detect the food responsible. The disease became reactivated only following the introduction of cereals. In order reduce the number of cereals to be excluded from the diet and to improve the patient’s quality of life, we offered the patient a gluten-free diet that maintained the EoE in remission.

Three months later, the patient returned for a check-up and re-ported that he had lost 3 kg with the 6FED, but had not regained the weight. He also reported eating all foods except those containing gluten. He made complaint of asthenia and a right upper quadrant abdominal pain that had lasted for 1 month. Blood test (Table 1) and chest/abdominal computed tomography scan were performed.



Elisa GT. et al: Eosinophilic esophagitis due to gluten diseaseExplor Res Hypothesis Med

The computed tomography scan showed hepatosplenomegaly and pleural effusion with atelectasis of the lower lobe of the left lung due to ischaemia and left portal vein thrombosis. The patient was admitted and given a final diagnosis of chronic myeloproliferative syndrome, of the essential thrombocytopenia type (JAK2-positive, calreticulin-negative), and deemed at high risk of thrombosis and hypothyroidism.

Discussion

Our patient suffered from classic EoE, very similar to the cases previously described (male, onset of symptoms in the 4th decade of life).6 In our patient, the EoE did not subside with high doses of IBPs, and, after explaining to him the possible treatments (cor-ticosteroids or diet), he chose the elimination diet.7 Since results of allergy testing against the most frequently involved foods were negative, the patient was prescribed a 6FED.5 In order to improve the quality of life of the patient, we followed what other authors have done with other foods, such as milk,8 and offered him the op-portunity to test whether gluten was responsible for his EoE.

The patient agreed to adhere to the same diet as if he were a patient with coeliac disease. After performing oesophagoscopy, we found that gluten was the responsible protein for the patient’s EoE. Therefore, even if he had to follow the diet indefinitely, he could eat rice and corn and gluten-free cereals, for which many super-markets have wide selections of currently. Although in this patient, gluten produced an eosinophilic inflammation of the oesophagus, it did not produce inflammation of the stomach or duodenum; in addition, we ruled out coeliac disease in this patient, as villous atrophy was not detected in the duodenal biopsies.

We know from our experience that when patients adhere to the 6FED diet they lose at least 2–3 kg in 6 weeks, but this weight is quickly recovered. In this patient, however, this did not happen and, instead, he complained of other symptoms. The subsequent studies showed at least one autoimmune disease (hypothyroidism), an increasingly common finding in patients with EoE.9 Our patient also had developed an associated haematologic malignancy, which is rare in patients with EoE. We have reviewed the literature and only found isolated cases of EoE as a paraneoplastic syndrome. These include a patient with ganglioneuroblastoma and another case of an oesophageal tumour compatible with the “classical variant” of inflammatory myofibroblastic tumour, with prominent

eosinophilic infiltrate from the lesional to the extralesional area consistent with EoE.4,10 We believe that patients with EoE have a risk of developing malignancies similar to that in the general population.

In conclusion, this is the first report of a case of EoE due to glu-ten without coeliac disease that presents the unusual comorbidities of hypothyroidism (an autoimmune disease) and essential throm-bocythemia (a neoplasm of haematologic origin).




Study concept and design (JRS), acquisition of data (YMD, LML, AEO), analysis and interpretation of data (JMS), drafting of the initial and final manuscript (JFFB), critical revision of the manu-script (RGR), study supervision (EGT), translation to English (YMD, LML, AEO).

References

[1] Roaldsnes C, Holst R, Frederiksen H, Ghanima W. Myeloproliferative neoplasms: trends in incidence, prevalence and survival in Norway. Eur J Haematol 2017;98(1):85–93. doi:10.1111/ejh.12788.

[2] Spergel JM. An allergist's perspective to the evaluation of Eosinophil-ic Esophagitis. Best Pract Res Clin Gastroenterol 2015;29(5):771–781. doi:10.1016/j.bpg.2015.06.011.

[3] Mansoor E, Cooper GS. The 2010-2015 Prevalence of Eosinophil-ic Esophagitis in the USA: A Population-Based Study. Dig Dis Sci 2016;61(10):2928–2934. doi:10.1007/s10620-016-4204-4.

[4] Prader S, Spalinger J, Caduff J, Hürlimann S, Rischewski J. Eosino-philic esophagitis as paraneoplastic syndrome in a patient with gan-glioneuroblastoma. Klin Padiatr 2015;227(3):173–175. doi:10.1055/s-0035-1547307.

[5] Lucendo AJ, Arias Á, González-Cervera J, Yagüe-Compadre JL, Guag-nozzi D, Angueira T, et al. Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosino-philic esophagitis: a prospective study on the food cause of the dis-ease. J Allergy Clin Immunol 2013;131(3):797–804. doi:10.1016/j.jaci.2012.12.664.

[6] Castro Jiménez A, Gómez Torrijos E, García Rodríguez R, Feo Brito F, Borja Segade J, Galindo Bonilla PA, et al. Demographic, clinical and allergological characteristics of Eosinophilic Esophagitis in a Spanish central region. Allergol Immunopathol (Madr) 2014;42(5):407–414. doi:10.1016/j.aller.2013.04.004.

[7] Dellon ES, Gonsalves N, Hirano I, Furuta GT, Liacouras CA, Katzka DA, et al. ACG clinical guideline: Evidenced based approach to the diag-nosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol 2013;108(5):679–692; quiz 693. doi:10.1038/ajg.2013.71.

[8] Leung J, Hundal NV, Katz AJ, Shreffler WG, Yuan Q, Butterworth CA, et al. Tolerance of baked milk in patients with cow's milk-mediated eosinophilic esophagitis. J Allergy Clin Immunol 2013;132(5):1215–1216.e1. doi:10.1016/j.jaci.2013.08.017.

[9] Lecouffe-Desprets M, Groh M, Bour B, Le Jeunne C, Puéchal X. Eo-sinophilic gastrointestinal disorders associated with autoimmune connective tissue disease. Joint Bone Spine 2016;83(5):479–484. doi:10.1016/j.jbspin.2015.11.006.

[10] Fassan M, Castoro C, Saenz AJ, Cagol M, Ninfo V, Rugge M. Inflamma-tory myofibroblastic tumor as adverse outcome of eosinophilic es-ophagitis. Endoscopy 2009;41(Suppl 2):E95–E96. doi:10.1055/s-2008- 1077646.

Table 1. Blood tests made to the patient

Items Results

Blood 605,000 platelets/mcL

RBC and WBC counts Normal

Coagulation Normal

Except fibrinogen 775 mg/mL

ESR 40 mm

Lupus anticoagulant Positive

GGT 262 U/L

LDH 700 U/L

Alkaline phosphatase 259 U/L

Tyroid Tests TSH:1.26 mcu/ml; T4:N

Antibodies of connective tissue diseases All Negative

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