Newsletter The Intensivist

Newsletter of

Intensive Care Chapter Indian Academy of Pediatrics

MY EM YO DE O AD C CA

Happy Diwali! Currently, India, in particular Mumbai and Delhi, are having an outbreak of Dengue Fever (DF) with several deaths being reported. An increasing number of cases require close monitoring due to risk of complications. This outline reviews several critical points in the basic evaluation and management of children having Dengue. The World Health Organization defines Dengue Hemorrhagic Fever (DHF) when Dengue illness is accompanied by positive tourniquet test, thrombocytopenia (less than 100,000/mm3) and hem concentration hematocrit >20% above baseline value. DF is an acute illness characterized by fever, retro-orbital headache, severe myalgia, and occasionally a rash, lasting from 5 to 7 days. During seasonal periods of Dengue in India (July to November), any infant or child presenting with fever and such other symptoms should be evaluated for Dengue. These cases should be thoroughly examined and closely followed with vital signs. Complete blood cell count (CBC) and initial Dengue antibody titers should be taken. A small percentage of patients with Dengue may progress to more severe forms of the disease, with hemorrhagic manifestations and/or shock. I would request all of you to report all cases to local authorities, so they may take preventive measures. It also gives me great pleasure to inform you that all the preparations for the Annual conference are complete. Dr. Santosh Soan and his team are working hard to make Pediatric Intensive Care annual conference a grand success. I would request all of you to attend in large numbers. In Executive Board meeting to be held at Mangalore, on 17th Nov. 2012 we are planning to pass a resolution to have a National CME, and 4 zonal CMEs, so we can have more activities throughout year. I am very keen to host an Asian conference or International conference of Pediatric Intensive Care. I would request all seniors to guide us in this regard. We must congratulate Dr Sunit Singhi who is a senior member of IAP-Pediatric Intensive Care Chapter for completing 7 years as Asian representative in World Federation of Pediatric Intensive and Critical Care Societies (WFIPICS) I was really happy to see the last issue of the newsletter with some good new ideas. You will agree with me that Dr. Anil Sachdev, the editor is doing a wonderful job. Friends, please come forward and be an active member of the Intensive Care Chapter and contribute in its growth and various activities especially Basic Pediatric Critical Care Course. Only with your participation and support can we grow faster. Yours truly,

Intensive Care Chapter

The Intensivist
July-September, 2012 Editor Anil Sachdev Chairperson Rajiv Uttam Chairperson Elect Santosh Soans Secretary Kamlesh Srivastava Treasurer Kundan Mittal Immediate Past Chairperson Nirmal Choraria Executive Members DP Nakate Karunakara BP Rashna Dass Hazarika Sanjay Bafna Vikas Taneja

Office Bearers

Message from the Secretary ............................ 01

Dr Kamlesh Shrivastava Secretary

Anil Sachdev Department of Pediatrics, Institute of Child Health Sir Ganga Ram Hospital, Rajindra Nagar, New Delhi-110 060 Email: anilcriticare@hotmail.com Website: www.piccindia.org
1

Address for Correspondence

Contents

Review Article Adaptive Support Ventilation ............................ 03 Hypertension in PICU.......................................... 07 Journal Scan Journal Scan .......................................................... 14 Case Report An Unusual Case of Pneumonia -----Lipoid pneumonia ...................................... 17 Drug Review Dexmedetomidine ............................................. 23

S C CS

Dear Colleagues,

T TH H

DIAN IN A E

Message from the Secretary

DIATR PE I F

Intensive Care Chapter Indian Academy of Pediatrics 2012

Office OfficeBearers Bearers

Chairman Elect rajivuttam@hotmail.com

Rajiv Uttam

Santosh T Soan
Chairman Elect drsoans@yahoo.co.in

Secretary kamlesh4511@rediffmail.com

Kamlesh Srivastava

Past Chairman nirmal_choraria@yahoo.com

Nirmal Choraria

Treasurer kundanmittal@yahoo.co.in

Kundan Mittal

Editor anilcriticare@hotmail.com

Anil Sachdev

nakated@yahoo.com

DP Nakate

Karunakara BP Rashna Dass Hazarika Sanjay Bafna

bpkaruns@gmail.com

rashnadass@rediffmail.com sajaybafna16@gmail.com Executive Members

drvikastaneja@yahoo.co.in

Vikas Taneja

AGM - Notice
Notice is hereby given for a General Body Meeting of IAP- Intensive Care Chapter to discuss various issues, as stated under: Venue : Dr. T MA PAI International Convention Centre, Mangalore Date : Saturday, 17th November, 2012 Time : 5.00 pm onwards Agenda 1. Opening remark by Chairperson Dr. Rajeev Uttam. 2. To read and confirm the minutes of last AGM in 2011. 3. Business arising out of minutes 4. To adopt the annual report read by Secretary. 5. To adopt the audited account for year 2011- 2012 and present the budget proposal for the year 2012-2013. 6. To discuss about National CME and Zonal CMEs. 7. To decide about next annual conference. 8. To decide about formation of IAP Mahrashtra chapter. 9. Welcome new officer bearers for year 2012. 10. Any other issue with the permission of chair. Dr Kamlesh Shrivastava Secretary

Review Article

Adaptive Support Ventilation

Rakesh Patel Critical Care Fellow, Department of Pediatrics, Institute of Child Health, Sir Ganga Ram, Rajinder Nagar, New Delhi 110060

Introduction
Adaptive support ventilation (ASV) is a newly developed closed loop dual control mode, using measured dynamic compliance and time constant, with an automated adjustment of tidal volume and respiratory rate combined to meet the preset minute ventilation. ASV is an advanced mode of ventilation, evolved from mandatory minute ventilation (MMV) implemented with adaptive pressure control. This mode automatically selects appropriate tidal volume (Vt) and frequency (f ) for mandatory breaths and appropriate Vt for supported breaths depending upon mechanics of respiration and target minute ventilation (MV). It was first described by Laubscher et al in 1994 (1, 2) and became commercially available in 1998 (Hamilton Galileo ventilator, Hamilton Medical AG)

disease i.e., stiff lungs, results in the selection of a ventilatory pattern with low TV and high f. On the other hand, a long RCe, typical of airway obstruction and/or lung emphysema, results in the selection of a ventilatory pattern with higher Vt and low f. The parameter RCe is also used to calculate the inspiratory time (Ti) of mandatory breaths: Ti will be longer when RCe is short (restrictive disease), and shorter when RCe is long (obstructive disease), thus allowing a longer expiratory time when exhalation is slower and intrinsic PEEP is more likely to develop. The ventilator continuously monitors the respiratory system mechanics and adjusts its settings accordingly. Depending on the patients spontaneous respiratory rate, ASV can work as pressure controlled ventilation (PCV), if there is no spontaneous breathing; as pressure synchronize intermittent mandatory ventilation (SIMV), when the patients respiratory rate is less than the target; or as pressure support ventilation (PSV), if the patients respiratory rate is greater than the target. ASV recognizes spontaneous breathing and automatically switches between mandatory pressure-controlled breaths and spontaneous pressure-supported breaths in patients. The pressure level is then adapted to attain the target Vt (within limits imposed by pressure alarms). Cycling-off criteria is flow based in the case of assisted ventilation or time based for mandatory inspiration. The ventilator adjusts its breaths to avoid air trapping by allowing enough time to exhale, to avoid hypoventilation by delivering Vt greater than the dead space, and to avoid volutrauma by avoiding large Vt Table 1). The ventilator controls pressure or volume during inspiration, but not simultaneously. It may switch from one control variable to another during a single breath or between breaths, which is designated as dual control. Dual control is designed to assure patient-ventilator synchrony by allowing as much flow as the patient demands, while attempting to guarantee a minimum Vt.

Mechanism
ASV is a pressure control mode and provides intermittent mandatory breaths. Adaptive support ventilation controls breaths in optimal (adaptive) manner which helps minimizing the mechanical work of breathing. The machine selects Vt and frequency for set percentage of MV set. The ventilator calculates normal required MV based on patients ideal weight (IBW) and estimated dead space. The clinician sets target percentage of MV that the ventilator will support: more than 100% MV if increased requirement, and less than 100% MV while weaning. The ventilator initially delivers test breaths (first 5 breaths) in which it measures the expiratory time constant (RCe) for respiratory system and then uses it with estimated dead space and normal MV to calculate breathing frequency and Vt. The underlying algorithm selects ventilatory parameters in order to minimize work of breathing (WOB) based on the principle that for each given level of alveolar ventilation, there is a most effective combination of Vt and respiratory rate while limiting peak inspiratory pressures (PIP) (3-5). The parameter RCe, obtained from simplified analysis of the expiratory flow-volume curve (6) is a measure of the actual status of the passive respiratory mechanics of the patient. A low RCe, typical of restrictive respiratory

Table 1: Inherent advantages of adaptive support ventilation Maintain at least pre-set minute ventilation Take spontaneous breathing into account Prevent tachypnea Prevent Auto PEEP Prevent excessive dead space ventilation Fully ventilate in apnoea or low drive

scenario and lung physiology (8). Patient ventilator interaction Tassaux et al (11) conducted a crossover prospective study comparing SIMV-PS with ASV in the early weaning period of ten patients with acute respiratory failure of diverse causes. The results demonstrated that at a similar level of MV, patients receiving ASV had a lower level of respiratory drive (P0.1), lower WOB (based on EMG respiratory muscle activity), and improved patientventilator interactions, compared to SIMV-PS. Another study also demonstrated improved patient ventilator interaction in patients of respiratory failure with ASV as compared to SIMV-PS mode (12). Duration of mechanical ventilation Two trials suggest ASV may decrease time on mechanical ventilation (13, 14). Cassina et al (15) conducted a prospective observational study of a cohort of 155 consecutive patients after fast-track cardiac surgery and conrmed the safety aspects of ASV. One hundred thirty-four patients (86%) were extubated within 6 hours. No reintubation due to respiratory failure was required. This ventilation mode allowed rapid extubation in suitable patients and may facilitate postoperative respiratory management. Manual adjustments in ventilator Petter et al (16) conducted a randomized controlled trial compared ASV with standard protocol, ASV led to fewer ventilatory adjustments but achieved similar post surgical weaning outcomes. Sulzer et al (14) reported reduced duration of tracheal intubation, fewer arterial blood gas analysis and less frequent changes in ventilatory settings in post cardiac surgery patients on ASV mode. Weaning in chronic lung disease ASV appropriately decreased ventilatory support in patients with chronic respiratory failure who tolerated a conventional weaning trial, suggesting that ASV may facilitate respiratory weaning (17). Weaning of chronic obstructive pulmonary disease patients with ASV compared to PSV does not decrease overall length of mechanical ventilation, ICU stay and mortality (18). However, in patients successfully weaned, the duration of weaning was significantly shorter with ASV. Hence, in patients with a more complicated weaning, ASV might provide considerable benefits and also reduce staff workload, as it reduces manipulation and time spent in adjusting the ventilator. In a step-down centre for chronically ventilated patients, Linton et al (19) conducted weaning trials using the ASV mode and demonstrated the economy of automated
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Settings
The operator needs to add following inputs into the machine: Patient height( to calculate ideal body weight) Gender % of normal predicted MV goal FiO2 PEEP Figure 1: The ASV screen as implemented on GALILEO, Hamilton. The ASV target graphic screen shows: mode; minute ventilation%; PEEP; fraction of inspiratory oxygen concentration; minute volume curve target volume; safety boundary; actual tidal volume/ respiratory frequency combination; and the optimal tidal volume/respiratory frequency combination with which the patient will be ventilated.

Clinical application
ASV is intended as a sole mode of ventilation from initial support to weaning. Theoretically it offers: automatic selection of ventilator settings automatic adaptation to changing patient lung mechanics less need for human manipulation of the machine improves synchrony and automatic weaning

Clinical evidence
Automatically adjusted settings In passive and paralysed patients, ASV selects different combinations of tidal volume respiratory rate based upon respiratory mechanics of the patient (8-10). While in actively breathing patient no difference was found in ventilator setting chosen by ASV for different clinical

weaning without the need for respiratory therapists or continuous attendance by intensivists. Twenty seven patients were placed on ASV at 90% of target minute ventilation on arrival, and were reduced by 10% weekly to 60% of target minute ventilation, if tolerated by the patients. Twelve patients were successfully weaned from the ventilator within 2 weeks to 2 months of admission in the rst twelve months following establishment of the facility. Decrease work of breathing ASV and work of breathing was analysed in 22 patients with respiratory failure. Patients were compared for WOB in terms of PTP (Pressure time product) and P0.1 (airway occlusion pressure at 0.1 second of inspiratory flow) at various MV percentages. It was found that minimal PTP and P0.1 were found at higher percentage (40%) of ASV target. (ASV target was defined as appearance of mandatory breaths at that percentage of MV). The authors proposed an incremental % MV trial until mandatory breaths appeared as a suitable approach to define the range that sufficiently reduce work of breathing (20). Other benefits A notable finding in one study was the reduction in apnoea and high-pressure alarms in the ASV group that the authors suggested could potentially improve the working environment of nurses (21). In variety of lung disease Belliato et al (22) tested ASV in patients with normal lungs and in those with restrictive lungs, in COPD patients and in a physical lung model, with a normal level of and an increased minute ventilation. In postoperative patients with normal lungs, the ASV selected a ventilatory pattern close to the physiological one. In COPD patients, the ASV selected a high expiratory time pattern, and in restrictive lungs, a reduced tidal volume pattern. In the model, the selection was similar. In the hyperventilation test, the ASV chose a balanced increase in both Vt and respiratory rate. The authors explained that ASV would select an adequate ventilatory pattern for a variety of lung conditions.

number of patients, underlining a possible risk for ventilator induced lung injury. Though ASV provides minimum Vt, it cannot guarantee a constant volume. One concern is that the ventilator cannot distinguish between improved pulmonary compliance and increased patient effort (27). To explain, the underlying problem is that ASV is not based on transpulmonary pressure (PL), and thus respiratory mechanics. PL equals the difference between the alveolar pressure and the pleural pressure (Ppl), and determines the degree of lung distension. In patients with a very active drive (due to fever, pain, anxiety, delirium or distress induced by underlying disease), the Ppl becomes more negative and the PL increases, while the Paw remains constant or decreased. The ventilator could mistakenly consider this situation as an improvement of the patients compliance, and thus reduce the supportive pressure, leading to insufficient ventilation support. Weaning time would be prolonged without adequate management. Overall, there are inconsistent findings with ASV that might be attributed to the different patient populations studied. Moreover, in short-time ventilated postoperative patients, a more advanced closed-loop controlled mode might not necessarily prevail over conventional modes. The underlying algorithms probably do not fully apply to the individual patients and dynamic changes of underlying condition. For instance, although a substantial effort has been made in order to calculate dead space, the resulting calculations remain estimates not necessarily reflecting the individual truth (28). Majority of clinical studies of ASV have been conducted in cardiothoracic patients, feasibility of ASV in different group of patients is yet to be studied extensively. The effect of ASV on mortality has not yet been studied.

Conclusions
The ASV mode is a newly developed dual control ventilator mode, and has the advantages of lung protection, the use of fewer medical personnel resources and facility, the weaning of both acutely and chronically ventilated patients. Despite the flexibility of this mode, a clear clinical evidence of superiority over conventional modes remains to be demonstrated; moreover a caveat for the risk of high tidal volume with increased risk for ventilator induced lung injury in patients with acute lung injury/ acute respiratory distress syndrome must be carefully considered. ASV and other dual-control adaptive pressure control modes cannot distinguish improving lung mechanics from a deranged ventilatory demand, which might lead to some patients being distressed or prolonging the weaning process without recognition and adequate management. Large randomized controlled studies of the ASV are needed to clarify the role of ASV in clinical practice.
5

Drawbacks
ASV delivers unsafe respiratory rate- Vt combinations in patients with acute ling injury(23). Arnal et al(8) observed that almost 20% of acute lung injury/acute respiratory distress patients could not be ventilated with this mode due to an airway pressure of more than 35 cmH2O, with an increased risk for ventilator induced lung injury (24,25). In another study on cardiac surgery patients, recently published by Dongelmans et al (26) the Vt was more than 8 ml/kg in a substantial

References
1. Laubscher TP, Frutiger A, Fanconi S, et al. Automatic selection of tidal volume, respiratory frequency and minute ventilation in intubated ICU patients as start up procedure for closed-loop controlled ventilation. Int J Clin Monit Comput 1994; 11:1930. 2. Laubscher TP, Heinrichs W, Weiler N, et al. An adaptive lung ventilation controller. IEEE Trans Biomed Eng 1994; 41:5159. 3. Otis AB. The work of breathing. Physiol Rev 1954; 34:449458. 4. Otis AB, Fenn WO, Rahn H. Mechanics of breathing in man. J Appl Physiol 1950; 2:592607. 5. Mead J. The control of respiratory frequency. Ann N Y Acad Sci 1963; 109: 724729. 6. Brunner JX, Laubscher TP, Banner MJ, et al. A simple method to measure total expiratory time constant based on the passive expiratory flow volume curve. Crit Care Med 1995; 23: 1117-1122. 7. Hamilton Medical AG. Adaptive Support Ventilation Users Guide. Switzerland: Hamilton Medical AG, 1999. 8. Arnal JM, Wysocki M, Nafati C, et al. Automatic selection of breathing pattern using adaptive support ventilation. Intensive Care Med 2008; 34:75 81. 9. Campbell RS, Sinamban RP, Johannigman JA, et al. Clinical evaluation of a new closed loop ventilation mode: adaptive supportive ventilation (ASV). Crit Care 1999; 3(S1):P83. 10. Belliato M, Palo A, Pasero D, et al. A. Evaluation of adaptive support ventilation in paralysed patients and in a physical lung model. Int J Artif Organs 2004; 27:709716. 11. Tassaux D, Dalmas E, Gratadour P, et al. Patient ventilator interactions during partial ventilatory support: a preliminary study comparing the effects of adaptive support ventilation with synchronized intermittent mandatory ventilation plus inspiratory pressure support. Crit Care Med 2002; 30:801807. 12. Forel JM, Roch A, Papazian L. Paralytics in critical care: not always the bad guy. Curr Opin Crit Care 2009; 15:5966. 13. Gruber PC, Gomersall CD, Leung P, et al. Randomized controlled trial comparing adaptive-support ventilation with pressure-regulated volumecontrolled ventilation with auto mode in weaning patients after cardiac surgery. Anesthesiology 2008; 109:8187. 14. Sulzer CF, Chiolero R, Chassot PG, et al. Adaptive support ventilation for fast tracheal extubation after cardiac surgery: a randomized controlled study. Anesthesiology 2001; 95:13391345. 15. Cassina T, Chiolero R, Mauri R, et al. Clinical experience with adaptive support ventilation for fast-track cardiac surgery. J Cardiothorac Vasc Anesth 2003; 17: 571-575.
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16. Petter AH, Chiolro RL, Cassina T, et al. Automatic respirator/weaning with adaptive support ventilation: the effect on duration of endotracheal intubation and patient management. Anesth Analg 2003; 97:17431750. 17. Linton DM, Potgieter PD, Davis S, et al. Automatic weaning from mechanical ventilation using an adaptive lung ventilation controller. Chest 1994; 106:18431850 18. Kirakli C, Ozdemir I, Ucar ZZ, et al. Adaptive support ventilation for faster weaning in COPD: a randomised controlled trial. Eur Respir J 2011; 38:774780. 19. Linton DM, Renov G, Lafair J, et al. Adaptive Support Ventilation as the sole mode of ventilatory support in chronically ventilated patients. Crit Care Resusc 2006; 8: 11-14. 20. Wu CP, Lin HI, Perng WC, et al. Correlation between the % MinVol setting and work of breathing during adaptive support ventilation in patients with respiratory failure. Respir Care 2010; 55:334341. 21. Petter A, Chiolero R, Cassina T, et al. Automatic respirator weaning with adaptive support ventilation: the effect on duration of endotracheal intubation and patient management. Anesth Analg. 2003; 97: 17431750. 22. Belliato M, Palo A, Pasero D, et al. Evaluation of adaptive support ventilation in paralysed patients and in a physical lung model. Int J Artif Organs 2004; 27: 709-716. 23. Dongelmans DA, Paulus F, Veelo DP, et al. Adaptive support ventilation may deliver unwanted respiratory rate-tidal volume combinations in patients with acute lung injury ventilated according to an open lung concept. Anesthesiology 2011; 114:11381143. 24. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342:1301 1308. 25. Ferguson ND, Frutos-Vivar F, Esteban A, et al. Airway pressures, tidal volumes, and mortality in patients with acute respiratory distress syndrome. Crit Care Med 2005; 33:2130. 26. Dongelmans DA, Veelo DP, Bindels A, et al. Determinants of tidal volumes with adaptive support ventilation: a multicenter observational study. Anesth Analg 2008; 107: 932937. 27. Branson RD, Chatburn RL. Controversies in the critical care setting. Should adaptive pressure control modes be utilized for virtually all patients receiving mechanical ventilation? Respir Care 2007; 52: 478-485. 28. Brewer L, Orr J, Pace N. Anatomic dead space cannot be predicted by body weight. Respir Care 2008; 53:885891.

Review Article

Hypertension in PICU
Ashish Kumar Simalti Critical Care Fellow, Department of Pediatrics, Institute of Child Health, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi 110060

A hypertensive emergency is a clinical diagnosis that is appropriate when marked hypertension is associated with acute target-organ damage; in this setting, lowering of blood pressure (BP) is typically begun within hours of diagnosis. For hypertensive urgency with no acute target-organ damage, BP lowering may occur over hours to days. The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents classified pediatric hypertension into various stages (1) (Table 1). The Joint National Committee on Detection, Evaluation, and Treatment of Hypertension, JNC7, has labeled acute severe elevation of BP above 180/120mmHg (about 20mmHg above the Stage II hypertension) as Hypertensive Crisis in adults (2). About 1% of all adults with a diagnosis of hypertension develop hypertensive crisis, of which 76% are hypertensive urgencies and 24% are hypertensive emergencies (3). Similar data in children is not available (4). Although the prevalence of primary hypertension has been increasing at an alarming rate particularly in adolescents and older children (5), the incidence of hypertensive crisis is very uncommon in pediatric patients with primary hypertension and its occurrence is more common in pediatric patients with secondary hypertension (6).

Table 1: Definitions of normal and elevated blood pressure in children Normal blood pressure Systolic and diastolic blood pressure below 90th centile Pre-hypertension Systolic or diastolic blood pressure above the 90th centile (or 120/80 mmHg), but below the 95th centile Systolic or diastolic blood pressure higher than or equal to the 95th centile, but lower than the 99th centile plus 5 mm Hg Systolic or diastolic BP higher than or equal to the 99th centile plus 5 mm Hg

Stage I hypertension

Stage II hypertension

Table 2: Causes of hypertension in children Renal Glomerulonephritis, Acute tubular necrosis, Pyelonephritis, Hydronephrosis, Hemolytic-Uremic syndrome, Obstructive uropathy, Congenital dysplastic kidneys, Multicystic kidneys, Polycystic kidney disease, Renal artery stenosis, Renal vein thrombosis, Wilms tumor, Diabetic nephropathy Cardiovascular system Coarctation of aorta, Takayasus arteritis, Moyamoya disease Endocrine system Cushings syndrome, Hyperthyroidism, Hyperparathyroidism, Congenital adrenal hyperplasia Pheochromocytoma Central nervous system Raised intracranial pressure, Brain tumors, Intracranial hemorrhage, Autonomic dysfunction Neuroblastoma, Encephalitis Autoimmune disorders Systemic lupus erythematosus, Polyarteritis nodosa, Rheumatoid arthritis, Goodpastures disease Wegeners Disease, Mixed connective tissue disorders Medications, toxins, substance abuse Corticosteroids, Tacrolimus, Cyclosporine, Erythropoietin, Amphetamines, Oral contraceptives Anabolic steroids, Phencyclidine, Vitamin D intoxication, Cocaine, Alcohol, Smoking, Lead, thallium, mercury toxicity Miscellaneous Pain, Hypervolemia, Obesity, Umbilical artery cauterization, Intrauterine growth retardation, Pregnancy, Hypercalcemia, Drug withdrawal like opiates, blockers, Clonidine

Etiology
The etiology of hypertension depends on patients age, onset (acute versus chronic), and duration (intermittent/ episodic or persistent). For example, conditions like coarctation of aorta, renal vein, or artery thrombosis predominate in neonates. However, renal parenchymal diseases, pregnancy, endocrine conditions, autoimmune diseases, medications, and substance abuse are important etiologies in older children and adolescents. Conditions like phaeochromocytoma can present with episodic or sustained hypertension whereas chronic glomerulonephritis has persistent/sustained hypertension (Table 2). In adults, majority of the cases of hypertensive crises are due to non adherence to prescribed medication, drug overdose, sudden withdrawal of antihypertensive medications, and so forth. In comparison to adults, majority of pediatric hypertensive crises are renal in origin (7).

Pathophysiology and Pathogenesis

Blood pressure is a product of cardiac output and systemic vascular resistance (SVR). Cardiac output is a product of heart rate and stroke volume. In turn, stroke volume is determined by preload, contractility, and afterload/SVR(8). The pathogenesis of hypertensive crisis is multifactorial and factors that have been implicated in the pathogenesis include fluid overload, sympathetic over activity, renin-angiotensin-aldosterone system activation, oxidative stress, endothelial dysfunction, and inflammation. There is a complex interaction between all these factors and all or some factors occurring simultaneously may be involved in the pathogenesis of hypertensive crisis (6). Autoregulation Autoregulation is the ability of blood vessels to dilate or constrict to maintain normal perfusion. In normotensive individuals, normal arteries can maintain relatively normal flow rates over a wide range of mean arterial pressures, usually 60 to 150 mm Hg. Chronic elevations of BP cause compensatory functional and structural changes in the arterial walls and shift the auto-regulatory curve (pressure vs flow) to the right. This allows hypertensive patients to maintain normal perfusion and to avoid excessive blood flow at higher levels of BP. When the BP increases above the auto-regulatory threshold, tissue damage occurs. The primary abnormality in patients with hypertensive emergencies is altered autoregulatory capacity, particularly in the cerebral and renal beds, which can deteriorate into frank arteritis and ischemia. An understanding of autoregulation is critical for therapy because the sudden lowering of BP into a range that would otherwise be considered normal may reduce it below the auto-regulatory capacity of the hypertensive circulation and lead to inadequate tissue perfusion, ischemia, and/or infarction (9). Sensorineural hearing is known to have occurred due to rapid reduction of blood pressure (10).

Table 3: Clinical features where hypertensive emergency must be suspected (11) Symptoms Headache Dizziness Excessive crying Epistaxis Failure to thrive Joint pain Convulsions Hemiplegia Altered sensorium Visual disturbance Table 4: Diagnostic workup in hypertensive emergency (11) General Hemogram Renal Function Test Chest X-ray ECG Serum Electrolytes Specific Ultrasound abdomen Echocardiography CT Scan Plasma Renin Urinary 17 ketosteroids Vinyl mandellic acid Serum catecholamines levels Signs Short stature, pedal edema, pallor Tachycardia, increased sweating, flushing Moon face, obesity Absent or delayed femoral pulses, Abdominal bruit Retinal changes Neurological deficit Personality changes

Urine microscopic and routine Intravenous pyelography

Pharmacologic management hypertensive emergency in PICU

When choosing pharmacological therapy, fastacting, intravenous, easily titratable antihypertensive medications are generally used. According to Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescent, the primary aim of antihypertensive treatment is to reduce the blood pressure to <95th percentile and to <90th percentile in the presence of co-morbid conditions like diabetes, cardiac, or renal disease. Furthermore, the mean arterial blood pressure should be lowered no more than 25% of the initial value in the first 1 hr and a gradual reduction should be obtained over the next 2448 hrs to normalize the blood pressure (12). Following is the list of antihypertensive medicines available to us (Table 5). The agent of choice for hypertensive emergencies in patients varies widely among practitioners (13). Sodium nitroprusside Sodium nitroprusside has been the drug of choice to treat hypertensive emergencies because of easy availability and longstanding experience among treating physicians. This agent is a potent arterial and venous vasodilator through the generation of cyclic guanine mono-phosphate. These vasodilatory effects
8

Evaluation
Hypertensive emergency needs immediate attention. The initial assessment should be directed towards identification of affected end organs and possible causes. History taking and examination should be brief and relevant (Table3). The diagnostic workup must be individualized according to the history and physical examination findings (Table 4). Complicated diagnostic tests and transport of patient to other departments for evaluation should not be done until BP is adequately controlled (11).

decrease both afterload and preload. Advantageous properties of this medication, and benefit of its use, are its short duration of action of 1 to 2 minutes and its half-life of 3 to 4 minutes. This property also makes the drug easy to titrate. However, abrupt cessation of the infusion results in a rapid increase in blood pressure (14). Because of its quick onset of action, invasive arterial blood pressure monitoring is recommended. Sodium nitroprusside increases intracranial pressure, which would be disadvantageous in patients with hypertensive encephalopathy or cerebrovascular accident. Sodium nitroprusside may also lead to cyanide poisoning. It contains 44% cyanide by weight that is released nonenzymatically from the parent drug and the amount released is dependent on the dose. Infusions at rates of greater than 4 g/kg/ min for 2 to 3 hours have led to cyanide levels within the toxic range. This medication is recommended for use only in patients who have normal renal and hepatic function and when other intravenous antihypertensive medications are not available. If higher infusions of sodium nitroprusside are needed, an infusion of thiosulfate should be used to prevent the accumulation of cyanide. Labetalol It is an intravenous non-selective -blocker that also possesses 1-blocking effects and is commonly used to treat hypertensive emergencies. It produces its antihypertensive effect by decreasing the heart rate and lowering systemic vascular resistance. This medication can be given as an intravenous bolus or as a continuous infusion. The hypotensive effects of labetalol begin within 2 to 5 minutes after an intravenous bolus and peak at 5 to 15 minutes. The effects can last for 2 to 4 hours. Because this medication does not have pure -blocking effects, the patients cardiac output is maintained. Labetalol does reduce peripheral vascular resistance because of its -blocking effects, and it does not reduce peripheral blood flow (15). Clinicians should be aware of the possible adverse effects associated with labetalol, especially the development of sinoatrial/atrioventricular nodal dysfunction, such as heart block. Extra consideration must also be taken for patients with a history of asthma, because of the possible development of bronchospasm due to the nonselective -receptor blockade. Esmolol Esmolol, an intravenous, cardio-selective -blocker, has a rapid onset and a short duration of action, which make titration easy. This medication lowers BP through a decrease the rate and contractility of the heart through the blockade of 1 receptors. Esmolol is given as an initial 0.5 to 1.0 mg/kg intravenous loading dose over 1 minute and is followed by a continuous infusion. It is an ideal agent for situations where the cardiac output, heart rate, and blood pressure are increased, especially
9

when a patient is experiencing acute pulmonary edema, diastolic dysfunction, acute aortic dissection, and acute postoperative hypertension. Caution should be used when this medication is given to patients with asthma. The American College of Cardiology and the American Heart Association also concluded that esmolol may be contraindicated in patients with decompensated heart failure and bradycardia (16). Nitroglycerin Intravenously administered nitroglycerin is a potent vasodilator, and when used in high doses, arterial tone is also affected (17). It reduces BP by reducing both afterload and preload. These effects are undesirable in patients with compromised renal and cerebral perfusion. It has an onset of action of 1 to 5 minutes and duration of action of 5 to 10 minutes after the continuous infusion is discontinued. Although nitroglycerin has pharmacokinetic properties similar to those of sodium nitroprusside, it is not considered a first-line agent for the treatment of hypertensive emergencies, primarily because of its side effects of reflex tachycardia and tachyphylaxis. Nitroglycerine is not as efficacious as sodium nitroprusside. However, it may be used as an adjunctive agent for hypertensive emergencies associated with myocardial ischemia or pulmonary edema. Nicardipine It is an intravenous dihydropyridine-derivative calcium channel blocker and produces its antihypertensive effects by vasodilation of coronary vasculature and relaxation of smooth muscle. This medication has high vascular selectivity and strong cerebral and coronary vasodilatory activity. It has an onset of action of 5 to 15 minutes and duration of action of 4 to 6 hours while half life is 1 hour. Due to these factors titration of dosage is more difficult. The dosing of this medication is independent of weight, which can be useful in most hypertensive emergencies, especially in high adrenergic states (18). Fenoldopam It is a unique agent among the intravenous antihypertensive medications. It is a dopamine D1receptor agonist that was approved in 1997 for hypertensive emergencies. This medication causes peripheral vasodilation by acting upon peripheral dopamine type 1 receptors. Fenoldopam also activates dopaminergic receptors on the proximal and distal tubules of the kidney, thereby inhibiting sodium reabsorption, resulting in diuresis and natriuresis. It has an onset of action of 5 minutes and duration of effect of 30 to 60 minutes. This medication improves creatinine clearance, urine flow rates, and sodium excretion in patients with and without normal kidney function (19). It is recommended in cases of acute pulmonary edema,

diastolic dysfunction, hypertensive encephalopathy, acute renal failure, and microangiopathic anemia. This drug may cause hypersensitive reaction due to the presence of sodium metabisulphate in the solution. This medication should also be avoided in patients with increased intraocular hypertension and glaucoma (20). Clevidipine The newest intravenous antihypertensive agent approved for hypertensive emergencies is clevidipine. This medication is a third-generation dihydropyridine calcium channel blocker that inhibits L-type calcium channels in a voltage-dependent manner. The BP lowering is dose dependent and rapid, with a short half life of 1 to 2 minutes, a quick onset of action of 2 to 4 minutes and a short duration of action of 5 to 15 minutes. These properties make this medication easy to titrate. Clevidipine lowers systemic vascular resistance and does not affect the venous capacitance vessels or cardiac filling pressures. When compared with sodium nitroprusside, it has greater effects on arterial vasodilatation and fewer effects on venodilatation (21). Although studies have not been conducted in patients with hepatic or renal impairment, the metabolism and elimination of clevidipine should not be affected by impairment of these organs.

target organ damage and need not be immediately treated in a hospital with antihypertensive drugs (23). Renal hypertensive emergency Normal renal autoregulation enables the kidney to maintain a constant renal blood flow and glomerular filtration rate for mean arterial pressures between 80 and 160 mm Hg (24). Many patients who present with hypertensive emergencies have microscopic hematuria or acutely worsened renal function; gross hematuria is less common but should trigger urologic evaluation after BP reduction has been achieved. A urinalysis and measurement of serum creatinine should be performed initially in the assessment of all patients with a very high BP, and the latter can be compared with values in the recent medical record to establish whether the deterioration in renal function is acute. During treatment for hypertensive emergencies, many patients with acute-on-chronic renal excretory dysfunction display a temporary increase in serum creatinine, even when BP is lowered carefully and correctly. Optimal drug therapy for hypertensive emergencies with renal signs or symptoms is controversial. Although nitroprusside is the drug with the lowest acquisition cost and longest track record, many physicians favor the dopamine-1 agonist, fenoldopam mesylate, which not only avoids potential cyanide and thiocyanate toxicity during prolonged infusions or high doses of nitroprusside, but also has some acute beneficial effects in the kidney like natriuresis, diuresis, and creatinine clearance (19). Neurologic hypertensive emergency In patients with a very high BP and neurologic abnormalities (including altered mental status),a thorough examination of the optic fundi by direct ophthalmoscopy is essential. Patients with papilledema or new hemorrhages or exudates have hypertensive emergencies and often manifest some degree of hypertensive encephalopathy. A thorough initial neurologic examination is also important to document the extent and severity of focal neurologic defects that could change during treatment and then be attributed to an overaggressive lowering of BP or an acute stroke, either of which would change therapy. The most difficult of these is hypertensive encephalopathy, typically a diagnosis of exclusion (25). Hemorrhagic and thrombotic strokes are usually diagnosed by demonstrating focal neurologic deficits and a corroborating computed axial tomographic or magnetic resonance imaging scan of the head. Hypertension associated with head trauma (Cushings reflex) usually has the characteristic history and corroborating physical findings, but the BP goal is controversial. The management of each of these neurologic conditions is somewhat different. Sodium nitroprusside is still the drug typically chosen for encephalopathy and can be used in other conditions.
10

Types of hypertensive emergencies

The type of ongoing acute target-organ damage makes a great deal of difference in the way a patient with a very elevated BP should be evaluated and treated. These are most easily arranged by the organ system being damaged: aorta, cardiac, hemorrhagic, obstetric, catecholamine excess states, renal, or neurologic. Because there is, in general, little overlap across these areas, it is easiest to consider each separately. The recommended process of care includes brief focused neurologic and cardiovascular examinations; direct ophthalmoscopy; and an electrocardiogram, urinalysis, and blood testing for renal function (eg, serum creatinine). Comparison of a patients current results with previous findings will allow an appropriate decision to be made about how acute the observed target-organ damage is. Although left ventricular hypertrophy has been detected more commonly in patients with a hypertensive crisis than in control subjects with echocardiography, an electrocardiogram is both quicker to obtain and interpret and less expensive (9, 22). The specific level of BP is not a necessary or sufficient condition for the diagnosis of a hypertensive emergency. Young patients with previously normal BPs can occasionally have acute target-organ damage caused by an elevated BP like in the setting of acute glomerulonephritis, at the same time many patients with chronic, but poorly treated, hypertension present with much higher BPs and yet have no acute

Nimodipine has both antihypertensive and anti-ischemic effects and has improved long-term outcomes in subarachnoid hemorrhage but not in ischemic stroke. The BP goal during treatment also depends on the presenting diagnosis: BP lowering is warranted and therapeutic in hypertensive encephalopathy Cardiac hypertensive emergency Pulmonary edema is one common presentation of hypertensive emergencies that directly involve the heart. Most patients present with dyspnea, anxiety, and/or chest pain, and are hypertensive at presentation, sometimes severely so. Lowering BP is probably a useful modality in this circumstance because it reduces myocardial oxygen demand. The usual order of infusion includes furosemide and then enalapril (which improves hemodynamic outcomes after pulmonary edema (26), followed by nitroprusside if needed. Intravenous nicardipine has been most commonly used after cardiac surgery. Like all vasodilators, all these drugs cause reflex tachycardia, but their coronary arterial dilator effects typically offset the increased cardiac oxygen demand. Obstetric hypertensive emergencies In pregnant adolescents, hypertensive emergencies are defined differently from those in non pregnant women. Normally, BP declines during the first trimester of pregnancy; as a result, hypertensive emergencies (and preeclampsia) are typically diagnosed at much lower levels of BP than in non pregnant women. Because of the risks of eclampsia to mothers and fetuses, obstetricians are much more vigilant about elevated BP readings than other physicians. Many of the usual drugs used for hypertension are contraindicated in pregnancy. Nitroprusside is metabolized to cyanide, which is especially toxic to fetuses. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are contraindicated in the second and third trimesters of pregnancy because of nephrotoxic and other potentially adverse (and even fatal) effects in fetuses. Magnesium sulfate, methyldopa, and hydralazine are the drugs commonly used, with oral nifedipine or -blockers being add-on drugs (27). Intravenous fenoldopam is currently being studied in pregnancy but does not yet have FDA Table 5: Antihypertensive drugs used in PICU.
Drug Sodium nitroprusside Dose and Route 0.510 g/kg/ min I.V Mechanism of action Acts by releasing nitric oxide

approval for this indication. No matter which drug is chosen, delivery of an infant typically lowers the new mothers BP and is often hastened by the obstetrician in preeclampsia or eclampsia. Hypertensive emergency caused by catecholamine excess True hypertensive emergencies due to an excess of catecholamines can be caused by pheochromocytoma (or other chromaffin tumor), monoamine oxidase (MAO) inhibitor crisis, and intoxication with cocaine or other drugs of abuse. Patients with catecholamine excess states caused by severe burns can be given a beta-blocker (alone), which has other beneficial effects on both metabolism and outcomes.(28) Treatment of hypertensive emergencies caused by pheochromocytoma or cocaine toxicity usually begins with an intravenous alfa-blocker (phentolamine), and the beta-blocker is added thereafter only if necessary.(9) Aortic Dissection Aortic dissection is rare in children and is managed differently from other hypertensive emergencies because of its very high short term risk for patients and both the lower target BP (systolic BP 120 mm Hg for adults and 50th centile for children) and the short time recommended for its achievement (<20 minutes).(29). Quickly controlling the systolic BP using both a b-blocker and a vasodilator (classically, nitroprusside) is very important, although a quick transfer to the operating room for surgical repair is generally preferred.

Conclusions
Hypertensive crisis is an important pediatric emergency associated with significant morbidity and mortality. Early diagnosis, aggressive but careful management depending on specific etiologies, and long-term followup will help in decreasing some of this burden. Both basic and clinical research efforts to further delineate risk factors, pathophysiology, and epidemiology should be prioritized. Thus improved knowledge will contribute to better therapies.

Duration of action 1-2 minutes

Adverse effects Hypotension, palpitations, headache, nausea, vomiting, raised intracranial pressure, thiocyanate and cyanide toxicity, thyroid suppression Flushing, hypotension, palpitations, angina, syncope, peripheral edema, headache, vomiting

Contraindication and precautions Intracranial hypertension

Nicardipine

13 g/kg/ min IV

Calcium channel blocker

1530 min; may last for up to 3-4 hrs 11

Requires large fluid volume

Esmolol

125500 g/ kg/min

Beta-blocker

1020 min

Bradycardia, hypotension, bronchospasm, skin necrosis after extravasation, Raynauds phenomenon, congestive cardiac failure, cocaine toxicity Bradycardia, hypotension, atrioventricular conduction disturbances, headache, asthma, nasal congestion Palpitations, flushing, tachycardia, fever, rash, headache, arthralgia, SLElike syndrome, positive ANA, peripheral neuropathy Tachycardia, hypotension, flushing, headache, hypokalemia, nasal congestion Headache, nausea, vomiting, hypotension Patients with lipid disorders and egg and soy protein allergies

Labetalol

0.253 mg/kg/ hr IV

Combined alpha and beta blocker

Up to 4 hrs

Hydralazine

0.10.6 mg/kg/ dose every 46 hrs IV

Direct vasodilatation of arterioles

14 hrs

Fenoldopam

0.81.2 g/kg/ min IV

Dopamine D1 receptor agonist

1 hr

Clevidipine

0.5-3.5 mcg/kg/ min IV

L-type calcium channel blocker

up to 15 minutes

Phentolamine

0.050.1 mg/ kg/dose IV (max 5mg per dose) 510 mcg/kg/ dose q 824 hrs IV

-adrenergic blocker

1530 min

Tachycardia, palpitations, hypotension, flushing, headache, nasal congestion, exacerbation of peptic ulcer Hypotension, hyperkalemia, oliguria, rash, angioedema, agranulocytosis, neutropenia, cough, fatal hepatic necrosis (rare) Flushing, hypotension, tachycardia, palpitations, syncope, peripheral edema, headache, thrombocytopenia, rash, urticaria, elevated liver enzymes Bradycardia, hypotension, rebound hypertension with abrupt withdrawal, sedation, dry mouth, Tachycardia, fluid retention, rash, headache, weight gain, pulmonary edema, Stevens-Johnson syndrome, photosensitivity, pericardial effusion Hypotension, chest pain, hyperkalemia, azotemia, headache, fever, syncope, diarrhea, flu-like illness Suprarenal aortic stenosis and B/L renal stenosis Avoid sudden discontinuation Supra-renal aortic stenosis and B/L renal stenosis; most valuable in neonatal hypertension

Enalapril

Angiotensin converting enzyme inhibitor

46 hrs

Nifedipine

0.10.25 mg/ kg/dose q 46 hrs (max 10 mg/dose) oral

Calcium channel blocker

48 hrs

Clonidine

0.05-0.1 mg/ dose orally

Central -agonist

68 hrs

Minoxidil

0.1-0.2 mg/kg/ day (max 5mg/ day) orally

Hyperpolarization of K+channels resulting in smooth muscle relaxation

Up to 24 hrs

Losartan

Dose for < 6 years is not established. Children >6 years 0.7 mg/kg once daily (max dose 100 mg/ day) orally

Angiotensin II receptor blocker

24 hrs

12

References
1. Falkner B, Daniels S. Summary of the fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Hypertension 2004; 44: 387388. 2. Jones D W, Hall J E. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure and evidence from new hypertension trials. Hypertension 2004; 43: 13. 3. Zampaglione B, Pascale C, Marchisio M, et al. Hypertensive urgencies and emergencies: prevalence and clinical presentation. Hypertension 1996; 27: 144147. 4. Kearney P M, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of Worldwide data. Lancet 2005; 365: 217223. 5. Sorof J M, Lai D, Turner J, et al. Overweight, ethnicity, and the prevalence of hypertension in school-aged children. Pediatrics 2004; 113: 475482. 6. Singh D, Akingbola O, Yosypiv I, et al. Emergency management of hypertension in children Int J Nephrol 2012 :doi:10,1155/2012/420247 7. Deal J E, Barratt T M, Dillon M J. Management of hypertensive emergencies. Arch Dis Child1992; 67: 10891092. 8. Singh M,. Mensah G A,Bakris G. Pathogenesis and clinical physiology of hypertension. Cardiol Clin 2010; 28: 545559. 9. Elliott W J. Clinical Features in the Management of Selected Hypertensive Emergencies. Prog Cardiovasc Dis 2006; 48: 316-325. 10. Chao TK. Sudden sensorineural hearing loss after rapid reduction of blood pressure in malignant hypertension. Ann Otol Rhinol Laryngol 2004; 113:73-75. 11. Singhi SC, Kohli V. Management of hypertensive emergencies. Indian Pediatr 1992; 29: 1181-1186. 12. Daniels S R. Summary of the fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Hypertension 2004; 44:387388. 13. Benson JE, Gerlach JT, Dasta JF. National survey of acute hypertensive management. Crit Care Shock 2008; 11: 154166. 14. Varon J, Marik PE. The diagnosis and management of hypertensive crises. Chest 2000; 118: 214227. 15. Pearce CJ, Wallin JD. Labetalol and other agents that block both alpha- and beta-adrenergic receptors. Cleve Clin J Med 1994; 61: 5969. 16. Hunt SA, Abraham WT, Chin M H, et al. ACC/AHA 2005 guideline update for the diagnosis and

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23. 24. 25. 26.

27.

28. 29.

management of chronic heart failure in the adult: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation 2005;112: 154235. Bussman WD, Kenedi P, von Mengden HJ, et al. Comparison of nitroglycerin with nifedipine in patients with hypertensive crisis or severe hypertension. Clin Invest 1993; 70: 10851088. Marik PE, Varon J. Hypertensive crises challenges and management. Chest 2007; 131: 19491962 Oparil S, Aronson S, Deeb GM, et al. Fenoldopam: a new parenteral antihypertensiveconsensus roundtable on the management of perioperative hypertension and hypertensive crises. Am J Hypertens 1999; 12: 653664. Shusterman NH, Elliot WJ, White WB. Fenoldopam, but not nitroprusside, improves renal function in severely hypertensive patients with impaired renal function. Am J Med. 1993; 95:161168. Kieler-Jensen N, Jolin-Mellgard A, Nordlander M.et al. Coronary and systemic hemodynamic effects of clevidipine, an ultra-short-acting calcium antagonist, for treatment of hypertension after coronary artery surgery. Acta Anaesthesiol Scand 2000; 44: 186194. Nadar S, Beevers DG, Lip GY. Echocardiographic changes in patients with malignant phase hypertension:The West Birmingham Malignant Hypertension Register. J Hum Hypertens 2005;19: 69-75. Phillips RA, Greenblatt J, Krakoff LR. Hypertensive emergencies. Prog Cardiovasc Dis 2002; 45:33- 48, Aggarwal M, Khan I A. Hypertensive Crisis: Hypertensive emergencies and urgencies. Cardiol Clin 2006; 24: 135146. Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet 2000; 356:411-417. Annane D, Bellissant E, Pussard E, et al. Placebo controlled, randomized, double-blind study of intravenous enalapril efficacy and safety in acute cardiogenic pulmonary edema. Circulation 1996; 94:1316-1324, Vermillion ST, Scardo JA, Newman RB, et a l. A randomized, double-blind trial of oral nifedipine and intravenous labetalol in hypertensive emergencies of pregnancy. Am J Obstet Gynecol 1999; 181: 858861, Herndon DN, Hart DW, Wolf SE, et al: Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001; 345: 1223-1229. Ouriel K. Descending thoracic aortic dissection: Clinical aspects and anatomic correlations. Semin Vasc Surg 2002;15: 83-88.

13

Journal Scan

Journal Scan
Sheikh Minhas Fellow Pediatric Critical Care, Department of Pediatrics, Institute of Child Health, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi 110060

Adherence to PALS Sepsis Guidelines and Hospital Length of Stay

Paul R, Neuman MI, Monuteaux MC, et al. Pediatrics 2012; 130:e273e280

Procalcitonin usefulness for the initiation of antibiotic treatment in intensive care unit patients
Layios N, Lambermont B, Canivet JL, et al. Crit Care Med 2012; 40: 23042309

Objectives: Few studies have evaluated sepsis guideline adherence in a tertiary pediatric emergency department setting. Authors sought to evaluate (1) adherence to 2006 Pediatric Advanced Life Support guidelines for severe sepsis and septic shock (SS), (2) barriers to adherence, and (3) hospital length of stay (LOS) contingent on guideline adherence. Methods: Prospective cohort study of children presenting to a large urban academic pediatric emergency department with SS. Adherence to 5 algorithmic timespecific goals was reviewed: early recognition of SS, obtaining vascular access, administering intravenous fluids, delivery of vasopressors for fluid refractory shock, and antibiotic administration. Adherence to each timedefined goal and adherence to all 5 components as a bundle were reviewed. A detailed electronic medical record analysis evaluated adherence barriers. The association between guideline adherence and hospital LOS was evaluated by using multivariate negative binomial regression. Results: A total of 126 patients had severe sepsis (14%) or septic shock (86%). The median age was 9 years (interquartile range, 316). There was a 37% and 35% adherence rate to fluid and inotrope guidelines, respectively. Nineteen percent adhered to the 5-component bundle. Patients who received 60 mL/ kg of intravenous fluids within 60 minutes had a 57% shorter hospital LOS (P = .039) than children who did not. Complete bundle adherence resulted in a 57% shorter hospital LOS (P = .009). Conclusions: Overall adherence to Pediatric Advanced Life Support sepsis guidelines was low; however, when patients were managed within the guidelines recommendations, patients had significantly shorter duration of hospitalization.

Objectives: To test the usefulness of procalcitonin serum level for the reduction of antibiotic consumption in intensive care unit patients. Design: Single-center, prospective, randomized controlled study. Setting: Five intensive care units from a tertiary teaching hospital. Patients: All consecutive adult patients hospitalized for >48 hrs in the intensive care unit during a 9-month period. Interventions: Procalcitonin serum level was obtained for all consecutive patients suspected of developing infection either on admission or during intensive care unit stay. The use of antibiotics was more or less strongly discouraged or recommended according to the Muller classification. Patients were randomized into two groups: one using the procalcitonin results (procalcitonin group) and one being blinded to the procalcitonin results (control group). The primary end point was the reduction of antibiotic use expressed as a proportion of treatment days and of daily defined dose per 100 intensive care unit days using a procalcitonin-guided approach. Secondary end points included: a posteriori assessment of the accuracy of the infectious diagnosis when using procalcitonin in the intensive care unit and of the diagnostic concordance between the intensive care unit physician and the infectious-disease specialist. Measurements and Main Results: There were 258 patients in the procalcitonin group and 251 patients in the control group. A significantly higher amount of withheld treatment was observed in the procalcitonin group of patients classified by the intensive care unit clinicians as having possible infection. This, however, did not result in a reduction of antibiotic consumption. The treatment days represented 62.6 34.4% and 57.7 34.4% of the intensive care unit stays in the procalcitonin and control groups, respectively (p = .11). According to the infectious-disease specialist, 33.8% of the cases in which no infection was confirmed, had a procalcitonin value >1g/L and 14.9% of the cases with confirmed
14

infection had procalcitonin levels <0.25 g/L. The ability of procalcitonin to differentiate between certain or probable infection and possible or no infection, upon initiation of antibiotic treatment was low, as confirmed by the receiving operating curve analysis (area under the curve = 0.69). Finally, procalcitonin did not help improve concordance between the diagnostic confidence of the infectious-disease specialist and the ICU physician. Conclusions: Procalcitonin measuring for the initiation of antimicrobials did not appear to be helpful in a strategy aiming at decreasing the antibiotic consumption in intensive care unit patients.

pressure ventilation, along with short acting -agonists and systemic steroids, can be safe, well-tolerated, and effective in the management of children with status asthmaticus.

Non-Invasive Ventilation for Severe Bronchiolitis: Analysis and Evidence

Lazner M R, Basu AP, Klonin H. Pediatric Pulmonology 2012 47:909916

Safety, efficacy, and tolerability of early initiation of noninvasive positive pressure ventilation in pediatric patients admitted with status asthmaticus: A pilot study
Basnet S, Mander G, Andoh J, et al. Pediatr Crit Care Med 2012; 13:393398

Objectives: (1) To examine whether infants with severe bronchiolitis, fulfilling criteria for further respiratory support, could be managed outside a Pediatric Intensive Care Unit (PICU) with non-invasive ventilation (NIV) alone. (2) To study the characteristics, clinical course and outcome of NIV responders and non responders to assess safety and efficacy and inform guideline construction. Hypothesis: Infants with severe bronchiolitis can be safely managed with NIV outside a PICU. Study Design: Retrospective case review. Patient Selection: Cohort of infants with objective evidence of severe bronchiolitis requiring respiratory support nursed in a Pediatric High Dependency Unit (PHDU) and/or Intensive Care Unit (ICU) between 2001 and 2007. Methodology: Analysis of patient characteristics and respiratory parameters at admission and initiation of ventilation, changes after 2 and 4 hr of NIV or invasive ventilation, complications, short and long-term outcomes were analyzed. Results: One thousand and thirty-five infants with bronchiolitis were admitted with 67 ventilation episodes identified from 65 patients. Fifty-five episodes, including 34 with apnea, were treated exclusively with NIV. Six infants failed to respond and were invasively ventilated. Six patients were invasively ventilated at presentation. Non-responders had a significantly higher rate of bacterial infection. Significant improvements in respiratory parameters in responders occurred by 2 hr and sustained at 4 hr. Duration of hospital stay, ventilation requirement and oxygen requirement were significantly shorter in responders. Short and longer-term follow up data did not identify any adverse effects related to NIV. Conclusions: NIV was effective in 80% of infants receiving respiratory support for severe bronchiolitis.

Objectives: Although noninvasive positive pressure ventilation is increasingly used for respiratory distress, there is not much data supporting its use in children with status asthmaticus. The objective of this study was to determine safety, tolerability, and efficacy of early initiation of noninvasive positive pressure ventilation in addition to standard of care in the management of children admitted with status asthmaticus. Study Design: A prospective, randomized, controlled, clinical trial. Patients: Twenty patients (118 yrs old) admitted to the pediatric intensive care unit with status asthmaticus. Methods and Main Results: Children were randomized to receive either noninvasive positive pressure ventilation plus standard of care (noninvasive positive pressure ventilation group) or standard of care alone (standard group). Improvement in clinical asthma score was significantly greater in noninvasive positive pressure ventilation group compared to standard group at 2 hrs, 48 hrs, 1216 hrs, and 24 hrs after initiation of interventions (p < .01). A significant decrease in respiratory rate at 24 hrs oxygen requirement after 2 hrs was noted in noninvasive positive pressure ventilation group as compared to standard group (p = .01 and p = .03, respectively). Although statistically not significant, fewer children in the noninvasive positive pressure ventilation group required adjunct therapy compared to standard group (11% vs. 50%; p = .07). There were no major adverse events related to noninvasive positive pressure ventilation. Nine out of ten patients tolerated noninvasive positive pressure ventilation through the duration of the study; noninvasive positive pressure ventilation had to be discontinued in one patient because of persistent cough. Conclusions: Early initiation of noninvasive positive
15

Lung Aeration Changes After Lung Recruitment in Children With Acute Lung Injury: A Feasibility Study
Boriosi JP, Cohen RA, Summers E, et al. Pediatric Pulmonology 2012; 47:771779

Rationale: There are several adult studies using computed tomography (CT-scan) to examine lung

aeration changes during or after a recruitment maneuver (RM) in ventilated patients with acute lung injury (ALI). However, there are no published data on the lung aeration changes during or after a RM in ventilated pediatric patients with ALI. Objective: To describe CT-scan lung aeration changes and gas exchange after lung recruitment in pediatric ALI and assess the safety of transporting patients in the acute phase of ALI to the CT-scanner. Methods: Authors present a case series completed in a subset of six patients enrolled in the previously published study of efficacy and safety of lung recruitment in pediatric patients with ALI. Intervention: RM using incremental positive endexpiratory pressure. Results: There was a variable increase in aerated and poorly aerated lung after the RM ranging from 3% to 72% (median 20%; interquartile range 6, 47; P = 0.03) (Fig 1). All patients had improvement in the ratio of partial pressure of arterial oxygen over fraction of inspired oxygen (PaO2/ FiO2) after the RM (median 14%; interquartile range: 8, 72; P = 0.03). There was a decrease in the partial pressure of arterial carbon dioxide (PaCO2) in four of six subjects after the RM (median --5%; interquartile range: --9, 2; P = 0.5). One subject had transient hypercapnia (41% increase in PaCO2) during the RM and this correlated

with the smallest increase (3%) in aerated and poorly aerated lung. All patients tolerated the RM without hemodynamic compromise, barotrauma, hypoxemia, or dysrhythmias.
Figure 1: CT scan of two patients taken before and after recruitment maneuver (RM)

Pre RM

Post RM

Pre RM

Post RM

Conclusions: Lung recruitment results in improved lung aeration as detected by lung tomography. This is accompanied by improvements in oxygenation and ventilation. However, the clinical significance of these findings is uncertain. Transporting patients in early ALI to the CT-scanner seems safe and feasible.

16

Case Report

An Unusual Case of Pneumonia -----Lipoid pneumonia

Preeti Anand Fellow, Pediatric Critical Care, Department of Pediatrics, Institute of Child Health, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi 110060

Exogenous lipoid pneumonia is pneumonitis resulting from the aspiration or inhalation of a fatty substance (1). We report a case of a child with history of ingestion of baby oil presenting as acute respiratory distress syndrome (ARDS).

Arterial blood gas at admission showed compensated respiratory alkalosis with metabolic acidosis with hypoxemia (pH-7.44, PaCO2 26.9, PaO2 52.4, HCO3 17.9, lactate 0.83). Chest x- ray showed bilateral nonhomogenous opacities (Fig 2).
Figure 2: Chest X Ray on admission to our center

Case report
10-month female infant, presented with complaints of accidental ingestion of 15 ml of baby oil one month prior to admission. She developed cough and one episode of vomiting after ingestion. She was noticed to have fever the next day which was mild to moderate grade, responding to antipyretics, not associated with chills and rigors. Fever was associated with tachypnea, dry cough and decreased oral intake. She was treated with oral antibiotics following, which the fever subsided but the tachypnea persisted. As the symptoms persisted she was given a trial of oral steroids and nebulization. The chest x-ray done outside showed diffuse bilateral haziness (Fig 1). She was referred to our institution with progressively increasing fever and respiratory distress.
Figure 1: Chest X ray done one month after ingestion

On admission to our hospital, the infant was found to be irritable but alert. She had tachypnea (60/min) and tachycardia (160/min) with blood pressure of 60/40 mm of Hg and SpO2 88% in room air and 90% on oxygen by non-rebreathing mask. The child had nasal flaring and subcostal and suprasternal retractions and auscultation of the chest revealed diffuse crackles. There were no cardiac murmurs, hepatosplenomegaly and neurological deficits.
17

In view of the increased work of breathing with borderline PaO2, BIPAP with non-invasive ventilator was initiated but child did not tolerate and became agitated and desaturated. So she was intubated and started on mechanical ventilation on pressure regulated volume control mode (PRVC) with FiO2 1.0, PEEP at 8 cm H2O increased upto 12 cm H2O, tidal volume 7 ml/kg, rate 25/min and inspiratory time of 33%. Serial blood gases showed respiratory acidosis with worsening PaO2/FiO2 ratio of < 100mmHg (pH-7.11, PaCO2 66.1mmHg, PaO2 81.5mmHg, HCO3 20.6mmol/L, lactate 0.57mmol/L). The ventilation rate increased to 35/min, tidal volume increased to 11ml/kg achieving PIP of 35 cm H2O and PEEP to 12 cm H2O. In view of the high peak pressures, progressive respiratory acidosis and worsening oxygenation on conventional ventilation necessitated shifting to high frequency oscillatory ventilation (HFOV; Sensormedics 3100A). Endotracheal aspirates sent on admission for lipid-laden macrophages was positive while the gram stain and culture were negative. The initial HFOV settings were FiO2 1.0, amplitude of 53 cm H2O, frequency of 9 Hz and MAP 27 cm H2O. The ABG showed improvement pH-7.298, PaCO2 33.9mmHg, PaO2 82.2mmHg, HCO3 16.2mmol/L, lactate 1.18mmol/L. The

FiO2 was gradually decreased to 0.6, amplitude decreased to 44 cm H2O, frequency of 9.0 Hz and MAP 26 cm of H2O. On the above settings the SpO2 improved to 98% and the heart rate settled at 132/min and the ABG status was pH-7.213, PaCO2 54.2mmHg, HCO3 21.3mmol/L, PaO2 104.1mmHg, lactate 0.83mmol/L. The HFOV amplitude was increased to 50 cm H2O, FiO2 decreased to 0.5 and MAP was decreased to 23 cm H2O. Gradually the settings were decreased and she was shifted to conventional ventilation on day 4 of admission to SIMV +PS (volume control) mode with FiO2 0.6, PEEP at 8 cm H2O, PS 12 cm, rate 20/min, tidal volume of 8ml/kg and inspiratory time of 33%. In view of the hemodynamic instability the child was given fluid boluses at 20ml/Kg and later started on inotrope support- dopamine at 10mcg/kg/min, which was later tapered and discontinued on day 2 of admission after which she remained hemodynamically stable. The IV antibiotics were continued for 14 days and later discontinued after repeat sepsis screen came negative. Initial investigations showed total leucocyte count 18800/mm3 with C- reactive protein of 6 mg/L and sterile blood culture. Flexible bronchoscopy with large volume lavage (with 50 ml saline) was done on day 7 of admission. Bronchoscopy showed whitish mucoid secretions all over the tracheobronchial tree (Fig3).
Figure 3: Flexible bronchoscopy showing mucoid secretion in segmental bronchus

during which child was oxygenated with simple mask to maintain SpO2 above 90%. Nasogastric feeding was started on day 4 of admission and an attempt was made to provide proteins and calories through enteral route. During her stay in the hospital child had undergone repeated broncho-alveolar lavages with 75-80 ml of saline on weekly basis. To avoid post lavage hypoxemia and increased work of breathing, only one lung lavage was done at a time. Child was started with azathioprine (2.5mg/kg) once a day and prednisolone 2mg/kg on alternate day on day 20 of admission. At the time of writing of this report, infant is on BIPAP (IPAP 10 cmH2O, EPAP 5 cmH2O) for 4 hrs with 2 hrs of simple mask oxygenation at 4-5L/min flow rate. She has gained only 700 gms of weight in 4 months inspite of high calorie feed and has developed clubbing of all fingers during her stay in the hospital and there is no radiological improvement in the serial chest radiographs. We could not give surfactant due to financial reasons.
Figure 4: CECT of the chest diffuse ground appearance with consolidation of right lower lobe

Lipoid pneumonia- Review of literature

Lipoid pneumonia (LP) is the result of a foreign bodytype reaction to the presence of lipid material within the lung parenchyma. Lipoid pneumonia is an uncommon entity and an autopsy series reported a frequency of only 1.02.5% (2). LP can be endogenous or exogenous based on the source of lipids. Endogenous lipid pneumonia results from accumulation of lipids within the intra-alveolar macrophages in the setting of bronchial obstruction, chronic pulmonary infection, pulmonary alveolar proteinosis, or fat storage diseases (3,4). The aspiration or inhalation of exogenous lipids like mineral oil (present in Johnson baby oil), animal fats and vegetable oils, lead to exogenous lipoid pneumonia.

Pale white colored (milky) broncho-alveolar lavage was obtained and sent for investigations and came positive for lipid-laden macrophages however the cultures were sterile. The ventilator requirements increased marginally after the procedure. She was started on methylprednisolone at 2mg/kg/day, which was discontinued after 7 days. CECT scan of chest showed extensive diffuse ground glass appearance, which was consistent with lipoid pneumonia (Fig 4). Repeat bronchoscopic broncho-alveolar lavage further helped decrease the ventilator settings and the child was successfully extubated on day 11 of admission to our center. This child was electively started on BIPAP intermittently for 4 hours with 2 hours of rest period
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Exogenous lipoid pneumonia

Exogenous lipoid pneumonia was first described by Laughlen (3,5) in 1925, when he reported the presence of oil droplets in the lung during the autopsies of three children and one adult who had received mineral oil

nose drops or oral laxatives during life (5). In 1929, Quinn and Meyer illustrated how aspiration of the oil failed to provoke two important protective responses of the airway-glottis closure and coughing, and by-passed mucociliary transport mechanism (6). Epidemiology Based on the presentation, exogenous lipoid pneumonia can be classified as acute or chronic. Acute exogenous lipoid pneumonia is due to acute ingestion of large quantities of petroleum based products (7,8). Acute pneumonitis in children is seen due to accidental ingestion of petroleum-based products. Chronic exogenous lipoid pneumonia usually results from repeated episodes of aspiration or inhalation of animal fat or mineral or vegetable oils over an extended period. It is usually seen in children with anatomic or functional defects, including mental retardation and cleft palate, as well as in infants when mineral oil is used as a lubricant to facilitate feeding (2). Chronic lipoid pneumonia has also been reported in patients without a predisposing anatomic or functional abnormality in swallowing, with a history of chronic use of mineral oil or petroleum-based lubricants and decongestants such as Vaseline (Unilever), Vicks VapoRub, and lip gloss (2,9). Several reports of lipoid pneumonia, especially in infants and small children, have originated from traditional folk remedies. In India, sesame seed was used to flush secretions out through the nose (10). In Saudi Arabia animal fats, such as ghee, are often fed forcibly to establish regular bowel habits or administered intranasally to treat coughs and colds (11,12). In Brazil mineral oil used to relieve partial smallbowel obstruction due to Ascaris lumbricoides (13). An Oriental practice is to instill medicated oil into the nose and then sniff it (14). In children, chronic exogenous lipoid pneumonia has been reported as a result of embolization after rectal or subcutaneous administration of mineral oils (15). Pathogenesis The development of parenchymal abnormalities in lipoid pneumonia is dependent on the type, amount, frequency, and length of time of aspirated or inhaled oils or fats. Mineral oil, being bland and nonirritating, can enter the tracheobronchial tree without stimulating glottic closure or the cough reflex, and, once there, is expelled with difficulty because it impairs the mucociliary transport system (5,16). Mineral and vegetable oils like sesame seed, poppy seed, and olive oil provoke minimal to mild inflammatory reaction and are largely removed from the lung by expectoration (17). The aspirated oil is emulsified and phagocytosed by alveolar macrophages. These oil filled macrophages reach the interlobular septum through the lymphatic channels and cause thickening of the alveolar walls and destruction of some alveoli. Later, fibrotic proliferation
19

results in decreased lung volume (18). Most of the oil coalesces, forming large fat drops surrounded by fibrous tissue and giant cells, creating a tumor mass known as paraffinoma (19). Repeated massive aspiration results in diffuse parenchymal consolidation. Animal fats, however, are hydrolyzed by lung lipases into free fatty acids, which trigger a severe inflammatory reaction that manifests as focal edema and intraalveolar hemorrhage (9). Fatty acids remain either in the alveolar spaces or are phagocytosed by macrophages, which then migrate to the interlobular septa. Regardless of location, the inflammatory response can destroy the alveolar walls and the interstitium, and the resultant fibrosis can occasionally progress to endstage lung disease. Clinical manifestations Acute exogenous lipoid pneumonia typically presents as cough, dyspnea, and low-grade fever that usually resolves with supportive therapy (2). Patients with chronic exogenous lipoid pneumonia are frequently asymptomatic on presentation and are usually identified because of an incidentally detected abnormality on radiologic imaging. Crackles, wheezes, or rhonchi may be heard on auscultation of the chest. Laboratory investigations reveal hypoxemia, leukocytosis and an increased erythrocyte sedimentation rate may occur, especially when the lipoid pneumonia or a complicating infection causes fever (16). In a study done by Balakrishnan (10) from India in 1973 on 15 children, acute onset of dyspnoea, cough, and fever mostly mild or moderate, sometimes severe were the most common presenting symptoms (present in 80%). Recurring lower respiratory infections were found at presentation in approximately 17% of the patients and one out of the 15 patients presented with diarrhea and failure to thrive. All cases had history of oil bath at home. A case report from Mexico (20) retrospectively reviewed the medical records of 16 patients who had presented from 1991 to 1996 with lipoid pneumonia. A history of ingestion of different kinds of vegetable oil was positive in 12 (75%). Ingestion of olive oil was present in 10 children (75%), most receiving it more than once. The clinical presentation ranged from mild symptoms to death. Cough was found to be present in 100% cases (16 children). Dyspnea or respiratory distress was seen in 93.7%. 68.7% (9 children) had recurrent pneumonia as a presenting complaint. Cyanosis was found in 9 children (53.2%). Unlike the other case series, fever, was an uncommon presentation in this case series (10,21). Less common presentations include chest pain, hemoptysis, weight loss, and intermittent fevers, perhaps due to the inflammatory reaction to oil or to secondary infection related to bronchiectasis or pneumonia (22). Radiological evidence of acute exogenous lipoid

pneumonia can be seen within 30 minutes of the episode of aspiration or inhalation, and pulmonary opacities can be seen in most patients within 24 hours (23). The opacities are typically ground glass or consolidative, bilateral, and segmental or lobar in distribution and predominantly involve the middle and lower lobes (24). Other findings include poorly marginated nodules, pneumatoceles, pneumomediastinum, pneumothorax, and pleural effusions (23,24). Pneumatoceles are seen in regions of ground-glass or consolidative opacities and typically manifest radiologically within 230 days after aspiration or inhalation, and are more common in patients who have aspirated or inhaled a large amount of mineral oils or petroleum-based products (25). Pneumothorax and pneumomediastinum are rare and have been reported to occur within 4 days after hydrocarbon aspiration and are associated with a poor prognosis. Computed tomography (CT) scan of chest shows alveolar consolidations of low attenuation values, ground glass opacities with thickening of intralobular septa (crazy paving pattern), or alveolar nodules (26,27). Magnetic resonance imaging (MRI) may reveal high signal intensity on T1-weighted imaging consistent with lipid content (28). The radiologic manifestations of acute exogenous lipoid pneumonia typically improve or resolve over time. Resolution of opacities usually occurs within 2 weeks to 8 months (7). The imaging features of acute and chronic lipoid pneumonia overlap (2). Chronic exogenous lipoid pneumonia manifests as ground glass or consolidative opacities involving one or more segments, typically with a peribronchovascular distribution with predominant involvement of the lower lobes. Chronic exogenous lipoid pneumonia may present as single or multiple nodules or masses that may or may not contain fat (2,3). These radiologic manifestations can improve slowly over time but typically remain stable even if the exposure to vegetable or mineral oils or animal fats is discontinued (2). Cor pulmonale results due to fibrosis and destruction of normal lung architecture. Diagnosis of lipoid pneumonia is established in a patient with history of mineral oil ingestion with presence of lipid-laden macrophages in BAL fluid and foci of fat attenuation within areas of consolidation on highresolution CT (25,29-31). Lipid-laden macrophages in BAL fluid (Fig 5) are considered to be the most important finding for the diagnosis of lipoid pneumonia (25,29,32).
Figure 5: Lipid Laden Macrophages

Endogenous lipoid pneumonia

Cholesterol pneumonia or golden pneumonia is an obstructive pneumonitis. The diagnosis of endogenous lipoid pneumonia is made by the characteristic histopathological findings. Macroscopically, the parenchyma has a characteristic yellowish discoloration due to the accumulation of lipid in the alveoli (33). Histologically, there is an accumulation of lipid-filled macrophages and eosinophilic proteinaceous material derived from degenerating cells, including surfactant from type II pneumocytes, in the alveoli distal to the bronchial obstruction. Endogenous lipoid pneumonia typically manifests radiologically as consolidative opacities distal to a central obstructing lesion (35). Unlike exogenous lipoid pneumonia, the accumulation of lipidrich cellular debris does not manifest radiologically as lipid-containing opacities, and the diagnosis is histopathologic. The spectrum of endogenous lipoid pneumonia includes pulmonary infections, lipid storage diseases, and pulmonary alveolar proteinosis (3).

Treatment
There is no consensus on the right treatment modality for lipoid pneumonia. Avoiding exposure, treating any underlying infection and supportive care are the most important in management of lipoid pneumonia (1,16). Steroid therapy is a modality that has been tried in the treatment of lipoid pneumonia (35-38). They help by limiting the inflammatory response and ongoing fibrosis (35). Indumati et al from India reported the case of a two and a half year old child with history of ingestion of machine oil. After 8 weeks of steroid therapy the tachypnea and oxygen requirements decreased and the steroids were tapered off by 10 weeks with almost complete radiological clearance in 5 months (35). Similarly, Annobil et al reported a series of five children aged between four months to four years with lipoid pneumonia following nasal instillation of olive oil, where prednisolone was used for a varying periods of two months to five months resulting in complete clinical and radiological recovery (36). Similarly steroids were used in adults with lipoid pneumonia leading to a complete recovery (37,38). Others however have reported no benefits with steroids (10). BAL is a successful strategy recommended in the treatment of pulmonary alveolar proteinosis but only few reports have shown good response of whole lung lavage in the treatment of adults with lipoid pneumonia and just one case-report in a child with exogenous lipoid pneumonia (39 -42). A case series from Brazil, evaluated 10 children with mineral oil aspiration leading to lipoid pneumonia.
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They performed therapeutic BAL weekly until BAL fluid was nearly transparent and the cell count returned to normal range values and concluded that multiple therapeutic BAL of children with lipoid pneumonia results in significant improvement of CT findings, oxygen saturation, restoration of BAL fluid cellularity and clinical recover without any evidence of respiratory distress at the end of treatment and 6 months after the last BAL (43). Lung lavage with emulsifying liquids have been used successfully with good outcomes in severe cases of lipoid pneumonia (41,44). Russo et al, from Italy, reported the use of 0.05% polysorbate-80 in Ringers lactate (at 20 l/lung) as an emulsifier of lipid for repeated bronchoalveolar lavage. However several other reports have not shown any benefit of bronchoalveolar lavage (10,45). Azathioprine has been used in treatment of idiopathic pulmonary fibrosis, primarily in patients failing response or those with adverse effects from the use of corticosteroids (46). Anectdotal responses have been noted in uncontrolled trials (47). Azathioprine has been used in 2mg/kg/day (upto maximum of 150mg/day) for 3-6 weeks. The combination of azathioprine and steroids has shown more benefits with enhanced survival in patients (48). Immunoglobulins have also been used for successful treatment of lipoid pneumonia (49). Surgical resection of nodules and masses has been tried for treatment of lipoid pneumonia (50). However it should be reserved in cases with high suspicion of carcinoma (50).

References
1. Simmons A, Rouf E, Whittle J. Not Your Typical Pneumonia: A Case of Exogenous Lipoid Pneumonia. J Gen Intern Med. 2007; 22: 16131616. 2. Baron SE, Haramati LB, Rivera VT. Radiological and clinical findings in acute and chronic exogenous lipoid pneumonia. J Thorac Imaging 2003; 18:217 224. 3. Betancourt SL, Martinez-Jimenez S, Rossi SE, et al. Lipoid pneumonia: spectrum of clinical and radiologic manifestations. Am J Roentgenol. 2010; 194: 103-109. 4. Woodhead M, Parkes WR. Disorders caused by other organic agents. In: Parkes WR, ed. Occupational lung disorders, 3rd ed. Oxford, United Kingdom: Butterworth-Heinemann, 1994, Pg778793. 5. Laughlen GG. Studies on pneumonia following nasopharyngeal injections of oil. Am J Pathol. 1925; 1:407-414. 6. Quinn LH, Meye OO. The relationship of sinusitis and bronchiectasis. Arch Otolaryngol. 1929; 10: 152-165. 7. Kitchen JM, OBrien DE, McLaughlin AM. Perils of fire eating: an acute form of lipoid pneumonia or fire eaters lung. Thorax 2008; 63:401- 439.
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8. Lifshitz M, Sofer S, Gorodischer R. Hydrocarbon poisoning in children: a 5-year retrospective study. Wilderness Environ Med 2003; 14:7882. 9. Seo JB, Im JG, Kim WS, et al. Shark liver oilinduced lipoid pneumonia in pigs: correlation of thin-section CT and histopathologic findings. Radiology 1999; 212: 8896. 10. Balakrishnan S. Lipoid pneumonia in infants and children in South India. BMJ. 1973; 4: 329- 331. 11. Annobil SH, Benjamin B, Kameswaran M, et al. Lipoid pneumonia in children following aspiration of animal fat (ghee). Ann Trop Paediatr. 1991; 11: 87-94. 12. Hugosson CO, Riff EJ, Moore CCM, et al. Lipoid pneumonia in infants: a radiographical-pathological study. Pediatr Radiol. 1991; 21: 193-197. 13. De Oliveira GA, Del Caro SR. Bender Lamago CM et al. Radiographic plain film and CT findings in lipoid pneumonia in infants following aspiration of mineral oil used in the treatment of partial bowel obstruction by Ascaris lumbricoides. Pediatr Radiol. 1985; 15:157-160. 14. Jenkins DW, Quinn DL. Lipoid pneumonia caused by an Oriental folk medicine. South Med J. 1984; 77: 93. 15. Rabah R, Evans RW, Yunis EJ. Mineral oil embolization and lipid pneumonia in an infant treated for Hirschsprungs disease. Pediatr Pathol .1987; 7: 447 455. 16. Banjar H. Lipoid Pneumonia: A Review. Bahrain Medical Bulletin. 2003; 25: 1-6. 17. Pinkerton H. The reaction to oils and fats in the lung. Arch Pathol 1928; 5: 380401. 18. Kennedy JD, Costello P, Balikian JP, et al. Exogenous lipoid pneumonia. Am J Roentgenol. 1981; 136:11451149. 19. Adkins D, Bensadoun ES. An 85-year-old man with a lung mass. Chest. 2004; 125: 1121-1123. 20. Furuya ME, Martnez I, Ziga-Vsquez G, et al. Lipoid Pneumonia in Children: Clinical and Imagenological Manifestations. Arch Med Res. 2000; 31: 4247. 21. Bromer RS, Wolman IJ, Ralph S et al. Lipoid pneumonia in infants and children. Radiology .1939; 32: 1-7. 22. Subramanian S, Kherdekar SS, Baby PGV, et al. Lipoid pneumonia with Cryptococcus neoformans colonization. Thorax. 1982; 37: 319-320. 23. Haas C, Lebas FX, Le Jeunne C, et al. Pneumopathies caused by inhalation of hydrocarbons: apropos of 3 cases. Ann Med Interne (Paris) 2000; 151:438447 24. Brechot JM, Buy JN, Laaban JP, et al. Computed tomography and magnetic resonance findings in lipoid pneumonia. Thorax 1991; 46: 738739 25. Bandla HP, Davis SH, Hopkins NE. Lipoid pneumonia: a silent complication of mineral oil aspiration. Pediatrics 1999; 103:E19 26. Lee KS, Muller NL, Hale V et al. Lipoid pneumonia: CT findings. J Comput Assist Tomogr. 1995; 19: 4851. 27. Meltzer E, Guranda L, et al. Lipoid pneumonia: a

preventable complication. IMAJ. 2006; 8: 3335. 28. Laurent F, Philippe JC, Vergier B, et al. Exogenous lipoid pneumonia: HRST, MR and pathologic findings. Eur Radiol. 1999; 9: 11901196. 29. Sias SM, Ferreira AS, Daltro PA, et al. Evolution of exogenous lipoid pneumonia in children: clinical aspects, radiological aspects and the role of bronchoalveolar lavage. J Bras Pneumol. 2009; 35: 839-845. 30. Agarwal R. Low-attenuation consolidationthe most characteristic finding in lipoid pneumonia. Eur J Intern Med 2006; 17: 307. 31. Zanetti G, Marchiori E, Gasparetto TD, et al. Lipoid pneumonia in children following aspiration of mineral oil used in the treatment of constipation: high resolution CT findings in 17 patients. Pediatr Radiol 2007; 37: 11351139. 32. Picinin IF, Camargos PA, Marguet C. Cell profile of BAL fluid in children and adolescents with and without lung disease. J Bras Pneumol. 2010; 36: 372-385. 33. Gaerte SC, Meyer CA, Winer-Muram HT, et al. Fatcontaining lesions of the chest. Radio Graphics 2002; 22: S61S78. 34. Tamura A, Hebisawa A, Fukushima K. Lipoid pneumonia in lung cancer: radiographic and pathological features. Jpn J Clin Oncol 1998; 28: 492496. 35. Indumathi CK, Vikram KS, Paul P, et al Severe Lipoid Pneumonia Following Aspiration of Machine Oil: Successful Treatment with Steroids. Indian J Chest Dis Allied Sci 2012; 54: 197-199. 36. Annobil SH, Tahir MEL, Kameswaran M, et al. Olive oil aspiration pneumonia (lipoid) in children. Trop Health 1997; 2: 383-388. 37. Chin NK, Hui KP, Sinniah R, et al. Idiopathic lipoid pneumonia in an adult treated with prednisolone. Chest 1994; 105: 956-957. 38. Hussain IR, Edenborough FP, Wilson RS, et al. Severe lipoid pneumonia following attempted suicide by mineral oil immersion. Thorax 1996; 51: 652-653. 39. de Blic J. Pulmonary alveolar proteinosis. Paediatr Respir Rev 2004; 5: 340342.

40. Chang HY, Chen CW, Chen CY, et al. Successful treatment of diffuse lipoid pneumonitis with whole lung lavage. Thorax. 1993; 48: 947948. 41. Wong CA, Wilsher ML. Treatment of exogenous lipoid pneumonia by whole lung lavage. Aust N Z J Med .1994; 24:734735. 42. Ciravegna B, Sacco O, Moroni C, et al. Mineral oil lipoid pneumonia in a child with anoxic encephalopathy: treatment by whole lung lavage. Pediatr Pulmonol. 1997; 23: 233237. 43. Sias SMA, Daltro PA, Marchiori E, et al. Clinic and Radiological Improvement of Lipoid Pneumonia With Multiple Bronchoalveolar Lavages. Pediatr Pulmonol. 2009; 44:309315. 44. Russo R, Chiumello D, Cassani G, et al. Case of Exogenous Lipoid Pneumonia: Steroid Therapy and Lung Lavage with an Emulsifier. Anesthesiology. 2006; 104:197198. 45. Gondouin A, Manzoni Ph, Ranfaing E, et al. Exogenous lipid pneumonia: a retrospective multicentre study of 44 cases in France. Eur Respir J.1996; 9: 14631469. 46. American thoracic society (ATS), and the european respiratory society (ERS). Idiopathic Pulmonary Fibrosis: Diagnosis and Treatment. International Consensus Statement. Am J Respir Crit Care Med.2000; 161: 646664. 47. Cegla, U. H. 1977. Treatment of idiopathic fibrosing alveolitis: therapeutic experiences with azathioprineprednisolone and D-penicillamineprednisolone combination therapy. Schweiz. Med. Wochenschr. 107:184187. 48. Raghu, G., W. J. Depaso, K. Cain, et al. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective, doubleblind randomized, placebo-controlled clinical trial. Am. Rev. Respir. Dis. 1991; 144: 291296. 49. Amato GM, Novara V, Amato G. Lipid pneumonia. Favorable outcome after treatment with intravenous immunoglobulins, steroids, cephalosporins. Minerva Pediatr 1997; 49: 163-169. 50. Bellenot F, Regnard JF, Babo P, et al. Pseudotumoral lipid pneumopathies: Apropos of six cases. Ann Chir 1991; 45: 715-718.

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Drug Review

Dexmedetomidine
Neha Bhandari Senior Resident, Department of Pediatrics, Institute of Child Health, Sir Ganga Ram Hospital, New Delhi 110060

Introduction
Dexmedetomidine was approved by the Food and Drug Administration in 1999 for the sedation of adults receiving mechanical ventilation in an intensive care setting. It provides sedation with minimal effects on respiratory function and may be used prior to, during, and following extubation. Based on its efficacy in adults, dexmedetomidine is now being explored as an alternative or adjunct to benzodiazepines and opioids in the pediatric intensive care setting. This review describes the studies evaluating the safety and efficacy dexmedetomidine especially in infants and children and provides recommendations on dosing and monitoring.

Figure 2: Clonidine chemical structure

Mechanism of action
The 2-adrenergic agonists are sub-classified into 3 groups: imidazolines, phenylethylamines and oxalozepines. Dexmedetomidine (Fig 1) and clonidine (Fig 2) are members of the imidazole subclass which exhibits a high ratio of specificity for the 2 versus the 1 receptor. Clonidine exhibits an 2: 1specificity ratio of 200:1 while that of dexmedetomidine is 1600:1 thereby making it a complete agonist at the 2 adrenergic receptor. Dexmedetomidine has a short half-life (2-3 hours vs. 12-24 hours for clonidine) and is commercially available for intravenous administration (1,2). Dexmedetomidine has activity at a variety of locations throughout the central nervous system. The sedative and anxiolytic effects of dexmedetomidine result primarily from its activity in the locus ceruleus of the brainstem. Stimulation of 2-adrenergic receptors at this site reduces central sympathetic output, resulting in increased firing of inhibitory neurons. The presence of dexmedetomidine at 2-adrenergic receptors in the dorsal horn of the spinal cord modulates release of substance P and produces its analgesic effects (4,5).
Figure 1: Dexmedetomidine chemical structure

At the recommended infusion rate of 0.2 to 0.7 mcg/kg/ hr, dexmedetomidine provides sedation with minimal effects on respiratory function and may be used prior to, during, and following extubation. In clinical trials of adults, it produced the desired level of sedation in approximately 80% of patients, without the use of additional agents. In those receiving midazolam or morphine, it allowed the dose of each agent to be reduced (4,5).

Pharmacokinetics
After intravenous (IV) administration, dexmedetomidine has a rapid distribution phase, with a distribution halflife of approximately 6 minutes in adults. It is extensively distributed, with a volume of distribution of 118 L and protein binding of 94%. Dexmedetomidine exhibits linear kinetics over the recommended dosage range of 0.2 to 0.7 mcg/kg/hr. It is extensively metabolized through both the cytochrome P450 enzyme system, by aliphatic hydroxylation via CYP2A6, and direct glucuronidation. These metabolites are eliminated in the urine (95%) and feces (4%). Dexmedetomidine has a terminal elimination half-life of approximately 2 hours and a clearance of 39 L/hr in adults. Dose reduction is recommended for patients with hepatic dysfunction (5). The majority of patients receiving dexmedetomidine were effectively sedated yet were easily arousable, a unique feature not observed with other sedatives(6). The pharmacokinetic profile of dexmedetomidine in children has been assessed in several studies and have demonstrated that pharmacokinetics is similar in adult and children (7-11).

Pharmacodynamics
Dexmedetomidine has a biphasic cardiovascular response. It does not appear to have any direct effects on the heart (3,12). The bolus of 1 mcg/kg dexmedetomidine
23

initially results in a transient increase of the blood pressure and a reflex fall in heart rate, especially in younger patients (13-15). Stimulation of alpha2-adrenoceptor in vascular smooth muscle seems to be responsible for the initial rise in the blood pressure, which can be attenuated by a slow infusion. However, even at slower infusion rates, the increase in mean arterial pressure over the first 10 minutes was shown to be in the range of 7%, with a decrease in heart rate between 16% and 18% (14). The initial response lasts for 5 to 10 minutes and is followed by a slight decrease in blood pressure due to the inhibition of the central sympathetic outflow. These effects may also be observed in the postoperative period, and can be easily managed with atropine, ephedrine and volume infusion (17). However, these effects may be deleterious in hypovolemic patients or patients with fixed stroke volume (18).The respiratory depression caused by dexmedetomidine has been reported to be much less than with other sedatives (19).

The ability of dexmedetomidine to produce hypotension or bradycardia may be magnified by administration with other drugs capable of producing those effects. In a study comparing midazolam and dexmedetomidine, the authors observed a case of bradycardia in a 5-weekold infant receiving both dexmedetomidine and digoxin (23). The patient had an atrioventricular septal defect and was given dexmedetomidine (0.5 mcg/kg loading dose followed by continuous infusion of 0.44 mcg/kg/hr) during mechanical ventilation for an acute respiratory syncytial virus infection. The patient continued to receive her home dose of digoxin (10 mcg twice daily) during hospitalization. The patients heart rate decreased from 133 bpm to 116 bpm during administration of the loading dose. It continued to decline to the mid90s, with periodic dips to 40 to 50 bpm. Heart rate returned to baseline within 1 hour of discontinuing dexmedetomidine. The authors theorized that the drugs produced bradycardia through an additive increase in vagal tone (3).

Adverse effects
The most significant adverse reactions associated with dexmedetomidine are hypotension, and bradycardia, resulting from its sympatholytic activity (3). However, dexmedetomidine should be used with caution in patients already at risk for arrhythmias or hemodynamic instability. Both sinus node and atrio-ventricular node function were affected. The authors recommended that dexmedetomidine should not be used during cardiac electrophysiologic studies (20). In most cases, dexmedetomidine-induced hypotension or bradycardia resolves with dose reduction and administration of IV fluid boluses (21). Transient hypertension has been reported with the administration of the loading dose due to initial vasoconstriction caused by stimulation of peripheral postsynaptic alpha2-adrenergic receptors. In clinical trials of adults, the rate of hypertension was similar in treated patients and controls (12% compared to 19%) (5).Clinically significant hypertension has been reported in isolated pediatric cases (22) but has not been common in larger case series.

Clinical experience
Over two dozen case series and studies have been published evaluating the safety and efficacy of dexmedetomidine in infants and children. Preliminary Experience Initial reports of the use of dexmedetomidine as a sedative in the pediatric population were published in two case series from the same institution (24,25). The first, published in 2002, described experience with dexmedetomidine in two children during mechanical ventilation, in one child during surgery, and in one other for procedural sedation (25). Infusion rates ranged from 0.25 to 0.7 mcg/kg/hr. Three patients achieved adequate sedation, but one 11year-old boy undergoing endoscopy required the addition of midazolam and ketamine before his procedure could be performed. Their second paper described dexmedetomidine use in five additional children (24,25). Three were given an IV loading dose of 0.5 mcg/kg over 10 minutes followed by an infusion of 0.25 mcg/kg/hr, titrated to response. The two remaining patients were given a single 0.5 mcg/kg IV bolus dose. All of the patients achieved the desired level of sedation. As in their initial case series, the children tolerated dexmedetomidine without significant adverse effects. Based on the successful use of dexmedetomidine in these two case series, the authors concluded that this agent deserved further study as a sedative for children. Use in critical care in children Chrysostomou et al (27) retrospectively reviewed their experience with dexmedetomidine infusions following cardiac and thoracic surgical procedures in 38 patients with a mean age of 8 1 year. Seven patients (18%) were
24

Drug interaction
Administration of dexmedetomidine with other sedatives and anesthetics typically produces a pharmacodynamic interaction resulting in enhanced sedation. This additive effect often allows for a reduction in the dose of sedative agents with a more significant adverse effect profile, such as benzodiazepines. Although dexmedetomidine undergoes metabolism by cytochrome P450 enzymes, no drug interactions involving this pathway have been identified. Dexmedetomidine does not alter responsiveness to non-depolarizing neuromuscular blocking agents (2,3).

less than 1 year of age and 33 (87%) were extubated and breathing spontaneously. The infusion was continued for 3 to 26 hours. There was mild to moderate sedation achieved 93% of the time and no to mild pain 83% of the time. Forty-nine doses of rescue agents were required for either sedation or analgesia (1.30.26 boluses per patient). Twenty-nine (60%) doses were required during the first 5 hours of the dexmedetomidine infusion. There was a trend toward requirement of higher dose in less than one year age. Tobias JD et al (28) also found similar results in his prospective randomized trial comparing midazolam and dexmedetomidine on thirty infants and children requiring sedation during mechanical ventilation. The authors speculated that dexmedetomidine may be less effective in younger patients. Procedural sedation Koroglu et al (29) randomized 80 children (1-7 years of age) to dexmedetomidine or midazolam during MR imaging. The quality of sedation was better and the need for rescue sedation was less (8 of 40 versus 32 of 40) with dexmedetomidine compared to midazolam. Similar efficacy was reported by Berkenbosch et al (30) in an open label trial during MRI in 48 pediatric patients ranging in age from 5 months to 16 years. Dexmedetomidine was administered as a loading dose of 0.5 g/kg over 5 minutes and repeated as needed to achieve the desired level of sedation. Effective sedation was achieved in all patients and the scan was completed without other agents. The largest experience with dexmedetomidine for procedural sedation comes from the Boston Childrens Hospital in a retrospective review of database (31). Mason et al presented data regarding dexmedetomidine for sedation in 62 children during radiological imaging. The time to achieve sedation varied from 6 to 20 minutes. Although heart rate and blood pressure decreased in all patients, no treatment was necessary and no value was less than the 5th percentile for age. No effects on respiratory function were noted. Two patients manifested significant agitation during the administration of the loading dose and were switched to other sedative agents (propofol or pentobarbital). The ongoing experience from the Boston Childrens Hospital has suggested that higher loading and infusion doses (up to 3 g/kg over 10 min) are needed to achieve a rapid onset and a high efficacy rate with no increase in adverse effects. Several small clinical trials have compared dexmedetomidine to propofol for pediatric procedural sedation (32-34). In 2005, 60 children undergoing MRI were randomized to receive either dexmedetomidine (1mcg/kg IV loading dose followed by 0.5 mcg/kg/hr infusion) or propofol (3 mg/kg IV loading dose followed by 100 mcg/kg/min infusion) (32). Adequate sedation occurred in 83% of the dexmedetomidine patients and 90% of the propofol patients. The onset of sedation,
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recovery time, and discharge time were all significantly shorter in the propofol group. More of the patients in the propofol group experienced adverse effects, with a lower mean arterial pressure, heart rate, and respiratory rate. Oxygen desaturation was reported in four propofol patients but none of the children receiving dexmedetomidine. Overall, both drugs were acceptable means of providing sedation, but neither offered a distinct advantage. A second comparison of dexmedetomidine and propofol was published in 2008 (33). Forty children between 1 and 10 years of age were randomized to receive either the combination of midazolam (0.1 mg/kg IV) and dexmedetomidine (1 mcg/kg IV followed by 0.5 mcg/kg/ hr) or propofol (250300 mcg/kg/min) for sedation during MRI. The authors concluded that dexmedetomidine, when used with midazolam, provided adequate sedation for MRI procedures in pediatric patients, but the combination resulted in more cases of prolonged recovery, bradycardia, and hypotension. Another paper comparing dexmedetomidine with propofol was published in 2009 (34). This retrospective study evaluated 52 children given dexmedetomidine and 30 children given propofol for sedation during MRI. Forty-one patients in the dexmedetomidine group and 26 patients in the propofol group had a previous diagnosis of obstructive sleep apnea (OSA). The authors concluded that dexmedetomidine was an acceptable alternative to propofol for pediatric MRI sleep studies, and may be a better alternative in children with OSA. Taking the results of these comparison trials as a whole, dexmedetomidine appears to provide a useful alternative to propofol for procedural sedation in children, with a longer time to recovery, but a lower incidence of adverse effects. Tobias et al. (28) reported that dexmedetomidine was not effective for upper GI endoscopy in an 11-yearold boy. Jooste et al (35) reported successful sedation with dexmedetomidine during fiberoptic intubation in 2 pediatric patients, both of whom were 10 years old, who presented for operative procedures and evidence of cervical spinal cord compromise. Similar success with dexmedetomidine for sedation during fiberoptic intubation of the trachea has been reported in adults. However, Jalowiecki et al (36) found dexmedetomidine to be ineffective during colonoscopy, associated with a high incidence of adverse effects, and to delay discharge in adults and therefore abandoned the study before completion. Munro et al. (37) reported their experience with dexmedetomidine during cardiac catheterization. Following premedication with midazolam and the placement of intravenous access with the inhalation of sevoflurane, the inhalational anesthetic agent was discontinued and dexmedetomidine administered. Five patients (25%) moved during local infiltration of the groin which did not require treatment or interfere with

cannulae placement. Twelve (60%) of patients received a propofol bolus during the procedure for movement, an increasing bispectral index number, or anticipation of a stimulus. Anecdotal experience suggests that a combination of dexmedetomidine with ketamine may be effective for painful invasive procedures (37). Scher and Gitlin reported the successful use of dexmedetomidine and ketamine for procedural sedation (awake fiberoptic intubation in an adult patient (38). Tosun et al (39) compared dexmedetomidine-ketamine with propofolketamine for sedation during cardiac catheterization in children with acyanotic congenital heart disease undergoing cardiac catheterization. Although sedation was managed effectively with both regimens, patients sedated with ketamine-dexmedetomidine required more ketamine. Despite the limited data, the combination of dexmedetomidine with ketamine makes pharmacologic sense as the two medications have the potential to balance the hemodynamic and adverse effects of the other. Dexmedetomidine may prevent the tachycardia, hypertension, salivation, and emergence phenomena from ketamine while ketamine may prevent the bradycardia and hypotension which has been reported with dexmedetomidine. Additionally, ketamine as part of the sedation induction may speed the onset of sedation and eliminate the slow onset time when dexmedetomidine is used as the sole agent and the loading dose is administered over 10 minutes. A second retrospective study evaluated 315 children with autism or other neurobehavioral disorders receiving dexmedetomidine for procedural sedation (40). The mean total dexmedetomidine dose used was 2.6 1.6 mcg/kg. Ten percent of the children were treated with dexmedetomidine alone; the others received dexmedetomidine with midazolam. The mean induction time was 7.8 3.5 minutes. The authors found no difference in dosing requirements between the children with autism and those with other conditions. Children 3 years of age or younger required doses that were, on average, 20% larger than those of the older children. All but four of the procedures were able to be successfully completed. Hypotension and bradycardia occurred in 9.5% and 20.3% of patients, respectively. As in the studies conducted in children receiving mechanical ventilation, dexmedetomidine appears to be an effective sedative for infants and children with neurologic impairment. Dexmedetomidine has also been used to provide sedation for children in a wide variety of other settings. Additional reports have documented the utility of dexmedetomidine in children requiring fiberoptic intubation and in children undergoing awake craniotomy, sevoflurane anesthesia, stereotactic radio surgery, and radiation therapy (41-45). Dexmedetomidine has also

been used for sedation during hypercyanotic spells in a neonate with tetralogy of Fallot, in the management of an infant undergoing iatrogenic opioid and benzodiazepine withdrawal, and in children and adolescents with cyclic vomiting syndrome (46-48).

Dosing and Administration

Recommended adult dosage range of 0.2 to 0.7 mcg/ kg/hr may also be used in children (24,25,32,33,41-49). Dexmedetomidine may be initiated with a loading dose of 1 mcg/kg given over 10 minutes, but some pediatric centers reduce or omit the loading dose in an effort to avoid bradycardia and hypotension. The infusion should be titrated to patient response, with a suggested maximum dose of 2 mcg/kg/hr. Dexmedetomidine is available in a 100 mcg/mL concentration in a 2 mL preservative-free vial. It may be prepared as a 2 to 4 mcg/ mL solution using normal saline.

Withdrawal
There were no reports of withdrawal or rebound, despite an average duration of 11 days and a range of 2 to 50 days. In 2005, the successful use of dexmedetomidine for a 4-day period in a child requiring mechanical ventilation following tracheal reconstruction for subglottic stenosis was described (49). In 2009, a retrospective study of 54 children given dexmedetomidine after cardiac surgery also found no adverse effects with prolonged use (50). The mean duration of administration was 16.7 hours, with a range from 1 to 112.5 hours. None of the patients exhibited withdrawal or rebound effects.

Conclusions
Dexmedetomidine is used as an adjunct to anesthetic agents because of the sedative, analgesic and anxiolytic and sympatholytic properties. Its benefits include limited effects on respiratory drive, a relatively short half-life, no significant drug interactions, and a generally mild adverse effect profile. It may be particularly useful in children with underlying neurologic disorders, who often develop agitation or adverse hemodynamic and respiratory effects with opioids or benzodiazepines. Dexmedetomidine appears to be well tolerated when used at recommended doses, but it has the potential to cause significant hypotension and bradycardia and should be used only when the patient can be appropriately monitored. While the case series and studies published to date suggest that this agent is appropriate for pediatric use, additional studies, including prospective clinical trials currently underway, are needed to further define the role of dexmedetomidine in pediatric intensive care.

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References
1. Tobias JD. Dexmedetomidine: Applications in pediatric critical care and pediatric anesthesiology. Pediatr Crit Care Med 2007; 8:115-131. 2. Virtanen R, Savola JM, Saano V, et al. Characterization of selectivity, specificity and potency of demedetomidine as an alpha2-adrenoceptor agonist. Eur J Pharmacol 1998; 150: 9-14. 3. Buck. L Marcia. Dexmedetomidine use in Pediatric intensive care and procedural sedation. J Pediatr Pharmaco Ther 2010; 15: 17-29. 4. Munoz R, Berry D. Dexmedetomidine: promising drug for pediatric sedation. Pediatr Crit Care Med 2005; 6: 493494. 5. Nelson LE, Lu J, Guo T, et al. The alpha 2 adrenoreceptor agonist dexmedetomidine converges on an endogenous sleep promoting pathway to exert its sedative effects. Anesthesiology 2003; 98: 428-436. 6. Venn RM, Bradshaw CJ, Spencer R, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia 1999; 54: 1136-1142. 7. Petroz GC, Sikich N, James M, et al. A phase I, two-center study of the pharmacokinetics and pharmacodynamics of dexmedetomidine in children. Anesthesiology 2006; 105:10981110. 8. Diaz SM, Rodarte A, Foley J, et al. Pharmacokinetics of dexmedetomidine in postsurgical pediatric intensive care unit patients: preliminary study. Pediatr Crit Care Med 2007; 8: 419424. 9. Vilo S, Rautiainen P, Kaisti K, et al. Pharmacokinetics of intravenous dexmedetomidine in children under 11 years of age. Br J Anaesth 2008; 100: 697700. 10. Potts AL,Warman GR, Anderson BJ. Dexmedetomidine disposition in children: a population analysis. Paediatr Anaesth 2008; 18:722730. 11. Potts AL, Anderson BJ, Warman GR, et al. Dexmedetomidine pharmacokinetics in pediatric intensive care - a pooled analysis. Paediatr Anaesth 2009; 19: 11191129. 12. Housmans PR. Effects of dexmedetomidine on contractility, relaxation, and intracellular calcium transients of isolated ventricular myocardium. Anesthesiology 1990; 73: 919-922. 13. Dyck JB, Maze M, Haack C, et al. The pharmacokinetics and hemodynamic effects of intravenous and intramuscular dexmedetomidine hydrochloride in adult human volunteers. Anesthesiology 1993; 78: 813-820. 14. Hall JE, Uhrich TD, Barney JA, et al. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg 2000; 90: 699-705. 15. Bloor BC, Ward DS, Belleville JP, et al. Effects of intravenous dexmedetomidine in humans. Hemodynamic changes. Anesthesiology 1992; 77: 1134-1142.
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16. Aantaa R, Kanto J, Scheinin M, et al. Dexmedetomidine, an alpha 2-adrenoceptor agonist, reduces anesthetic requirements for patients undergoing minor gynecologic surgery. Anesthesiology 1990; 73: 230235. 17. Jalonen J, Hynynen M, Kuitunen A, et al. Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting. Anesthesiology 1997; 86: 331-345. 18. Ebert TJ, Hall JE, Barney JA, et al. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000; 93: 382-394 19. Belleville JP, Ward DS, Bloor BC, et al. Effects of intravenous dexmedetomidine in humans.Sedation, ventilation, and metabolic rate. Anesthesiology 1992; 77: 1125-1133. 20. Hammer GB, Drover DR, Cao H, et al. The effects of dexmedetomidine on cardiac electrophysiology in children. Anesth Analg 2008; 106: 7983. 21. Tobias JD. Bradycardia during dexmedetomidine and therapeutic hypothermia. J Intens Care Med. 2008; 23: 403408. 22. Erkonen G, Lamb F, Tobias JD. High-dose dexmedetomidine-induced hypertension in a child with traumatic brain injury. Neurocrit Care 2008; 9: 366369. 23. Berkenbosch JW, Tobias JD. Development of bradycardia during sedation with dexmedetomidine in an infant concurrently receiving digoxin. Pediatr Crit Care Med 2003; 4: 203205. 24. Tobias JD, Berkenbosch JW. Initial experience with dexmedetomidine in paediatric-aged patients. Paediatric Anaesth 2002; 12: 171175. 25. Tobias JD, Berkenbosch JW, Russo P. Additional experience with dexmedetomidine in pediatric patients. South Med J 2003; 96: 871875. 26. Belleville JP, Ward DS, Bloor BC, Maze M. Effects of intravenous dexmedetomidine in humans:I Sedation, ventilation, and metabolic rate. Anesthesiology 1992; 77: 1125. 27. Tobias JD, Berkenbosch JW. Sedation during mechanical ventilation in infants and children: dexmedetomidine versus midazolam. South Med J 2004; 97: 451-455. 28. Chrysostomou C, Zeballos T. Use of dexmedetomidine in a pediatric heart transplant patient. Pediatr Cardiol 2005; 26: 651-654. 29. Koroglu A, Demirbilek S, Teksan H, et al. Sedative, hemodynamic and respiratory effects of dexmedetomidine in children undergoing magnetic resonance imaging examination: preliminary results. Br J Anaesth 2005; 94: 821-824. 30. Berkenbosch JW, Wankum P, Tobias JD. Prospective evaluation of dexmedetomidine for noninvasive procedural sedation in children. Pediatr Crit Care Med 2005; 6: 435-439.

31. Mason KP, Zgleszewski SE, Dearden JL, et al. Dexmedetomidine for pediatric sedation for computed tomography imaging studies. Anesth Analg 2006; 103: 57-62. 32. Koroglu A, Teksan H, Sagir O, et al. A comparison of the sedative, hemodynamic, and respiratory effects of dexmedetomidine and propofol in children undergoing magnetic resonance imaging. Anesth Analg 2006; 103: 6367. 33. Heard C, Burrows F, Johnson K, et al. A comparison of dexmedetomidine-midazolam with propofol for maintenance of anesthesia in children undergoing magnetic resonance imaging. Anesth Analg 2008; 107:18321839. 34. Mahmoud M, Gunter J, Donnelly LF, et al. A comparison of dexmedetomidine with propofol for magnetic resonance imaging sleep studies in children. Anesth Analg 2009; 109:745753. 35. Jooste EH, Ohkawa S, Sun LS. Fiberoptic intubation with dexmedetomidine in two children with spinal cord impingements. Anesth Analg 2005; 101:1238 1248. 36. Jalowiecki P, Rudner R, Gonciarz M, et al. Sole use of dexmedetomidine has limited utility for conscious sedation during outpatient colonoscopy. Anesthesiology 2005; 103:269-273. 37. Munro HM, Tirotta CF, Felix DE, et al. Initial experience with dexmedetomidine for12 diagnostic and interventional cardiac catheterization in children. Pediatr Anesth 2007; 17:109-112. 38. Scher CS, Gitlin MC. Dexmedetomidine and lowdose ketamine provide adequate sedation for awake fibreoptic intubation. Can J Anesth 2003; 50:607-610. 39. Tosun Z, Akin A, Guler G, et al. Dexmedetomidineketamine and propofol-ketamine combinations for anesthesia in spontaneously breathing pediatric patients undergoing cardiac catheterization. J Cardiothor Vasc Anesth 2006; 20:515-519. 40. Lubisch N, Roskos R, Berkenbosch JW. Dexmedetomidine for procedural sedation in children with autism and other behavior disorders.

Pediatr Neurol 2009;41: 8894. 41. Avitsian R, Lin J, Lotto M, et al. Dexmedetomidine and awake fiberoptic intubation for possible cervical spine myelopathy: a clinical series. J Neurosurg Anesth 2005; 17:97-99. 42. Ard J, Doyle W, Bekker A. Awake craniotomy with dexmedetomidine in pediatric patients. J Neurosurg Anesth 2003; 15:263266. 43. Ibacache ME, Munoz HR, Brandes V, et al. Singledose dexmedetomidine reduces agitation after sevoflurane anesthesia in children. Anesth Analg 2004; 98: 6063. 44. Fahy CJ, Okumura M. Sedation for paediatric stereotactic radiosurgery: the dexmedetomidine experience. Anaesth Intensive Care 2004; 32: 809 811. 45. Shukry M, Ramadhyani U. Dexmedetomidine as the primary sedative agent for brain radiation therapy in a 21-month old child. Paediatr Anaesth 2005; 15:241242. 46. Senzaki H, Ishido H, Iwamoto Y, et al. Sedation of hypercyanotic spells in a neonate with tetrology of Fallot using dexmedetomidine. J Pediatr (Rio J) 2008; 84: 377380. 47. Finkel JC, Elrefai A. The use of dexmedetomidine to facilitate opioids and benzodiazepine detoxification in an infant. Anesth Analg 2004; 98: 16581659. 48. Khasawinah TA, Ramirez A, Berkenbosch JW, et al. Preliminary experience with dexmedetomidine in the treatment of cyclic vomiting syndrome. Am J Therapeut 2003; 10: 303307. 49. Buck ML, Willson DF. Use of dexmedetomidine in the pediatric intensive care unit. Pharmacotherapy 2008; 28: 5157. 50. Bejian S, Valasek C, Nigro JJ, et al. Prolonged use of dexmedetomidine in the pediatric cardiothoracic intensive care unit. Cardiol Young 2009; 19:98104. 51. Hammer GB, Philip BM, Schroeder AR, et al. Prolonged infusion of dexmedetomidine for sedation following tracheal resection. Paediatr Anaesth 2005;15:616 620.

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Minutes of Annual General Body Meeting 2011

Minutes of Annual General Body Meeting 2011 of The Indian Academy of Pediatrics, Intensive Care Chapter Date: 18th November, 2011 Time: 6 PM Venue: Hyderabad International Convention Centre Names of the members present in the meeting: 12. Dr. Vikas Taneja 1. Dr. V.R.N Reddy 13. Dr. M P Jayakrishnan 2. Dr. Girish H C 14. Dr. Manas Ranjan Sahoo 3. Dr. Pritesh Nagar 15. Dr. Bijoy Kumar Meher 4. Dr. Vomsidhar Kedar 16. Dr. J Ebor Jacob 5. Dr. Chinmay Beheva 17. Dr. Madhumati Otiv 6. Dr. Shrishu R Kamath 18. Dr. Rajiv Agarwal 7. Dr. Indira Jayakumar 19. Dr. Preetha Joshi 8. Dr. S. Shuba 20. Dr. Shikhar Jain 9. Dr. Rajakumar PS 10. Dr. Rakshay Sethi 21. Dr. Anjul Dayal 22. Dr. Farhan Shaik 11. Dr. Sunil Patil 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. Dr. Vishram Buche Dr. V.S.V Prasad Dr. Bala Ramachandran Dr. Satish Deopujari Dr. Praveen Khilnani Dr. Soonu Udani Dr. Suchitra Ranjit Dr. Krishan Chugh Dr. Rajiv Uttam Dr. Santosh Soane Dr. Karunakare BP

The 13th annual general body meeting of the Indian Academy of Pediatrics Intensive Care Chapter was held on 18th November 2011at the Hyderabad International Convention Centre. The minutes of the meeting were maintained by the Secretary Dr. Anil Sachdev himself. The meeting was put in order by the Chairperson of The Intensive Care Chapter Dr. Nirmal Choraria with a welcome note. This was followed by the presentation of the annual report on the activities and achievements and financial report 2011 of the chapter by the secretary Dr. Anil Sachdev. The agenda for the meeting which was circulated to all members prior to the AGM was presented by the Chairman Dr. Nirmal Choraria. A. The salient features of constitution of the Intensive care chapter were presented and all members agreed to increase the number of elected posts of office bearers with the addition of post of 2 vice chairpersons, one joint secretary and one nominated post of Chief Editor. After cordial discussion, the duration of 2 years for the post of secretary, Joint secretary and treasurer was passed. Also the post of Joint secretary and treasurer will be reserved for the members of Delhi. The immediate past Chairperson of the chapter will also be the member of the executive. All these important issues were discussed by the present members and finally passed by the AGM. B. The Chair person suggested having a permanent office to coordinate the chapter activities and he asked the present members for the options and suggestions. When he did not find any concrete proposal, the name of Sir Ganga Ram Hospital was suggested. Dr Satish Deopujari had reservation about the establishment of permanent office of the Chapter in Delhi at Sir Ganga Ram Hospital. He suggested rotating the location of the office to the place from where chairperson would be elected. Other members suggested relocation of office after a period of fixed time. So it was decided by the AGM to locate the IAP-Intensive Care Chapter at Sir Ganga Ram Hospital for a period of 5 years. The proposal was seconded by Dr. Suchitra Ranjit from Chennai and Dr. Vikas Taneja from Delhi. C. The candidate for the post of Chief Editor will be nominated by the AGM. Dr. Shekhar Venketraman from Pittsburg, USA, suggested that the selection of the Chief Editor should be based on the credential of the candidate and not by the popularity. Dr. Krishan Chugh from Delhi suggested formation of credential committee for the selection of Chief Editor. It was proposed by Dr. Praveen Khilnani that the Executive Committee 2012 will form the credential committee and select Chief Editor and two associate editors. A formal credential assessment form will be prepared by the Executive Committee. The nominated candidates will form the Editorial Board and present to the Executive Committee which will take final decision. D. The total annual expenses allowed to the Executive Committee is Rs. 2.5 lacs/year excluding the expenses for the publication of The Intensivist. The Chairperson and secretary can jointly sanction up to Rs 50,000/ on single occasion. For the expenses involving more than Rs 50,000/, the permission of the executive will be sought.
29

E. It was proposed to increase the Life membership fee to Rs. 1500.00 from Rs 1000.00 from Jan 2012. F. It was proposed to start Associate membership for onetime fee of Rs 1000.00 for a period of 5 years with no voting rights and the member shall receive electronic version of The Intensivists. This was suggested to encourage members of other medical branches especially anaesthesia, cardiology, pediatric surgery, adult intensivists and critical care nurses. G. Honorary membership for any suitable candidate should be proposed by 5 members of the IAP-Intensive Care Chapter to the Chairperson and secretary and the proposal should be passed by the AGM. The Honorary member will have no voting rights but can be appointed as an advisor in any of the chapter committees. H. The registration fee for the fellows joining IAP Critical Care Fellowship programme in any of the recognised institution is to be increased to Rs 12500/ and Rs 2500/ will be contributed to the Pediatric Intensive Care Chapter. I. It was also proposed by Dr Praveen Khilnani those Rs 500/ from the fee collected from each delegate for attending the Basic Pediatric Intensive Care Course should be given to the IAP Intensive Care Chapter. The proposal was seconded by Dr Soonu Udani and Dr Bala Ramachandran. J. It was proposed to start Pediatric Intensive Care Nursing Course and name of Dr. Nirmal Choraria as convener of this course was proposed by Dr. Soonu Udani and was seconded by Dr Praveen Khilnani. K. It was also decided that Pediatric Critical Care Council will carry out and coordinate all the academic activities of the chapter. L. Mr. Suresh Kathpaliya of HBS Advisors LLP from Delhi is the official auditor of the IAP-Intensive Care Chapter and will be responsible for the maintainence of the accounts. At the end the Chairperson thanked all the present members for their suggestions and support. This report of the minutes of the AGM at HICC Hyderabad has been prepared by Dr. Anil Sachdev, Secretary 2011.

Notice
To, All Office Bearers, All Executive board members, IAP- Pediatric Intensive Care Chapter

Notice is hereby given for an Executive Board Meeting of IAP- Pediatric Intensive Care Chapter to discuss various issues, as stated under: Date: 17th November, 2012 Venue: Dr. TMA PAI International Convention Centre, Mangalore Timing: 11am - 11. 45 pm Agenda 1. To discuss the Date, Venue & time for next EB meeting. 2. To discuss National CME, Zonal CMES in 2012- 2013. 3. To discuss about next annual conference 4. To consider any other matter with permission of the chair. Dr Kamlesh Shrivastava Secretary IAP - Intensive Care Chapter
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32