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1 Annals of Clinical & Laboratory Science, vol. 43, no. 2, 2013 Available online at Pericardial Effusion and Cardiac Tamponade in Neonates: Sudden Unexpected Death Associated with Total Parenteral Nutrition via Central Venous Catheterization 163 Mikako Warren 1, Karen S. Thompson 2, Edwina J. Popek 1, Hannes Vogel 3, and John Hicks 1 1 Department of Pathology, Texas Children s Hospital and Baylor College of Medicine, Department of Pathology, Houston, TX; 2 Department of Pathology, Kapi olani Medical Center for Women and Children, University of Hawaii John A. Burns School of Medicine, and Clinical Laboratories of Hawaii Honolulu, Hawaii; 3 Department of Pathology, School of Medicine, Stanford University Medical Center, Palo Alto CA, USA Abstract. Background: Total parenteral nutrition (TPN) via central venous catheter (CVC) is used routinely to provide adequate nutrition for neonates, especially those with very low birth weights (VLBWN). Pericardial effusion and cardiac tamponade (PCE/CT) is a potentially life-threatening CVC complication. Design: This autopsy study presents the gross and histopathologic findings in 5 neonates receiving continuous TPN via CVCs, who suddenly and unexpectedly died from PCECT. Results: The study population included five neonates (age 4-29 days, 3 males, 2 females, 4 VLBWN neonates, 1 full-term neonate). Chemical analysis of the milky-white PCE fluid showed high triglyceride levels ( mg/dl) consistent with intralipid. Right atrial microscopic examination with the four VLBWNs showed interstitial edema and dilated lymphatics (n=4), atrial thrombus (n=1), and focal fibrinous epicardial exudate (n=1). The fullterm neonate RA revealed focal myocyte coagulative necrosis, acute organizing hemorrhage, focal collagen deposition, myocardial hypertrophy, and endocardial thickening. Conclusions: Right atria in PCE/CT demonstrated marked interstitial edema and dilated fine vascular channels. Endocardial injury with permeation of hyperosmotic TPN fluid into the interstitium and egress into the pericardial sac is hypothesized as the etiology of PCE/CT. Recognition of PCE and impending CT in neonates with CVCs for TPN with expedient intervention may avoid sudden unexpected deaths. Key words: central venous catheter, cardiac tamponade, intralipid, total parenteral nutrition, neonate Introduction Total parenteral nutrition (TPN) with intravenous lipid emulsion (intralipid) via a central venous catheter (CVC) is necessary to provide adequate nutrition for very low birthweight neonates (VLBWN) and for those who cannot take nutrition orally. It is widely used in neonatal intensive care units (NICU). Reported complications of CVC include local and systemic infections, arrhythmias, intracardiac thrombosis, systemic and pulmonary embolization, endocarditis, myocardial perforation, pericardial effusion, pleural effusion, pulmonary infarction, and pulmonary hemorrhage [1-4]. Address correspondence to John Hicks, MD, PhD, DDS; Department of Pathology, Texas Children s Hospital, Baylor College of Medicine, 6621 Fannin St, AB1195, Houston, TX 77030; phone: ; fax: ; e mail: hicks@bcm.edu Although rare, pericardial effusion with cardiac tamponade (PCE/CT) in the neonate is one of the serious complications and carries a high mortality rate. A worldwide literature search (PubMed, January 1966 through November 2012) revealed a large number of reported cases of PCE/CT related to CVC use since the 1970s, when this device was first introduced. The estimated prevalence of PCE/CT is reported to be 1 to 3% with a fatality rate of 30-50% in single institution and multicenter retrospective surveys [5-11]. A significant number of PCE/CT cases have been reported to be due to myocardial damage and perforation of the right atrium (RA) by CVC tip. During the 1990s, concerns about CVC tip positioning were expressed /13/ by the Association of Clinical Scientists, Inc.

2 164 Annals of Clinical & Laboratory Science, vol. 43, no. 2, 2013 [10-15]. In response to reports of deaths attributed to PCE/CT, manufacturers recommended that the CVC tips not be placed in the RA. The 2001 Manchester Report from the United Kingdom recommended that all central venous lines inserted specifically for parenteral nutrition in neonates should be placed outside the cardiac chambers [11]. In 2002, the FDA (U.S. Food and Drug Administration) recommended that the catheter tip should not be placed in the right atrium, and that the neonate s movements should be minimized in order to keep the catheter from migrating into the RA [13]. Even after these recommendations were released, neonatal PCE/CT cases related to CVC use continued to be reported. Among the reported cases were some with appropriate CVC tip positioning [5, 9, 16, 17]. Few studies describe the histopathology of the RA wall [18-20, 22] in neonates with cardiac tamponade associated with CVCs undergoing autopsy. Findings have included evidence of myocardial damage and/or perforation, such as myocardial necrosis and mural thromboses. In most of these cases, the CVC tips were lodged in or were in close proximity to the RA and the RA wall. No histopathologic findings have been reported in the cases with appropriate CVC tip positioning. Study Design We evaluated five neonates (gestational ages of weeks; age at death 4-29 days of life), who experienced sudden unexpected death and underwent autopsy. All neonates had CVCs inserted and died secondary to pericardial effusion comprised of milky-white fluid. Positions of the CVC tips were confirmed in these cases by visual inspection during the autopsy examination and/or by radiologic imaging. This is the first autopsy series of neonatal PCE/CT related to CVCs that describes right atrial histopathologic findings in all cases, and includes a case with appropriate CVC tip positioning. This study was submitted for institutional review board and was placed in the autopsy exemption category. Case Reports: Case 1. The patient was a 13 day-old former 25-2/7 week gestational age (GA) female neonate born to a G3P4 mother. The pregnancy was complicated by placenta previa and premature rupture of membranes. Chorioamnionitis was suspected. The patient was born via Cesarian section with Apgar scores of 2 at one minute and 7 at five minutes. The birth weight was 580 grams. The patient was intubated and surfactant was given. Umbilical artery and vein catheters (UAC/UVC) were inserted, and dopamine and insulin drips were begun. Antibiotics were administered for E. coli sepsis. TPN was begun on the third day of life. Over the next few days, the patient did well and was extubated to nasal cannula with continuous positive airway pressure (CPAP). Antibiotics were discontinued. Insulin and dopamine drips were weaned. On the 11th day of life, the patient became suddenly bradycardic and cyanotic. Despite maximal resuscitative effort, the patient expired and underwent complete autopsy examination to determine the cause of death. The autopsy revealed a milky-white effusion distending the pericardial sac. The CVC tip was in the RA and in close contact with the myocardium. The PCE fluid was aspirated from the intact pericardial sac, and the CVC was tested with a gentle saline infusion using the catheter port. The saline challenge showed an intact line with no leakage noted within the pericardial sac or thoracic cavity. Gross examination demonstrated an RA with no evidence of perforation, rupture, or dehiscence. The microscopic examination of the entirely submitted right atrium revealed mild interstitial edema and dilated fine vascular channels, especially in the epicardial soft tissues. No ischemic changes, myocardial necrosis, intramural thrombosis, hemorrhage, or inflammation were seen. Case 2. The patient was a 12 day-old former 26 week GA male twin born to a 25 year-old G2P1 mother via emergency Cesarean-section secondary to footling breech position. The birth weight was 860 grams. The Apgar scores were 6 at one minute and 7 at 5 minutes. The patient was intubated and surfactant was given. UAC and UVC were inserted, and insulin and dopamine drips were started. TPN was begun on the third day of life. A patent ductus arteriosus (PDA) was ligated on day 4 of life without complications. The patient did well over the next several days, tolerating lower ventilator settings and requiring lower doses of vasopressors. On the 12 th day of life, the patient was noted to have a sudden bradycardial episode with a heart rate to 80

3 Pericardial Effusion and Cardiac Tamponade in Neonates 165 beats per minute (bpm). Aggressive resuscitation was undertaken with no response. The patient subsequently expired and underwent complete autopsy examination to determine the cause of death. Autopsy examination revealed a milky-white effusion distending the pericardial sac. PCE fluid was aspirated from the pericardial sac and sent for chemical analysis, revealing a triglyceride level of 717 mg/dl, consistent with TPN intralipid. The central line was tested with a gentle saline infusion using the CVC port. The saline challenge showed an intact line with no leakage noted into the pericardial sac or thoracic cavity. The CVC tip was within the RA and in close contact with the RA wall. No grossly identifiable lesions were present within the RA. The microscopic examination of the completely submitted RA showed interstitial edema and focal areas of early intramural thrombus formation. There was a small area of the myocardium in close proximity to the CVC tip that showed a moderately ischemic appearance. Interstitial edema and dilated fine vascular channels in the epicardial soft tissue were present. No myocardial necrosis, hemorrhage, or inflammation was noted. Case 3. The patient was an 18 day-old former 22 to 24 week GA male born to G3P2 mother with a history of Fusobacterium-associated chorioamnionitis. Birth weight was 580 grams and Apgar scores were 4 at one minute and 6 at five minutes. The patient was intubated and surfactant was given. UAC and UVC were inserted, and dopamine and insulin drips were begun. TPN was administered from the third day of life onward. A head ultrasound revealed left grade IV and right grade III interventricular hemorrhage with a midline shift. The patient experienced electrolyte abnormalities and had Staphylococcus aureus sepsis, which was treated with Vancomycin and Gentamicin. A Candidal skin infection was treated topically. The infant s condition continued to deteriorate with bilateral cystic encephalomalacia, requiring increasing ventilator and pressor support. The central access line was changed to a peripherally inserted central catheter (PICC) during the hospital course. On the 18 th day of life, the patient suddenly developed progressive hypotension followed by progressive bradycardia. Despite resuscitative efforts, the patient expired and underwent complete autopsy examination to determine the cause of death. Autopsy findings revealed a markedly distended pericardial sac filled with 8 ml of milky-white fluid. Chemical analysis of the fluid revealed a triglyceride level of 744 mg/dl, consistent with TPN intralipid. The CVC coursed through the right femoral vein and the tip was proximal to the RA on a postmortem radiograph. No perforation or grossly identifiable lesions were noted on gross examination of the RA. However, microscopic examination of the entirely submitted RA revealed a fibrinous epicardial exudate. In addition, interstitial edema and dilated fine vascular channels in the epicardial soft tissue were present. No ischemic changes, myocardial necrosis, intramural thrombosis, hemorrhage or inflammation were seen. Case 4. The patient was a 4 day-old former 26-4/7 week GA male born to G3P2 mother via Cesarean section for preterm labor and breech presentation. The pregnancy was complicated by uterine leiomyomata. The birth weight was 671 grams. Apgar scores were 2 at one minute and 7 at five minutes. The patient was intubated and surfactant was given. An UAC/UVC was inserted. TPN was begun on the first day of life. The patient was extubated and placed on nasal CPAP. Echocardiogram showed a patent PDA and the patient was treated with 3 doses of a nonsteroidal anti-inflammatory medication, with PDA closure confirmed three days later. On the fourth day of life, the patient developed sudden onset of bradycardia and severe hypotension. Radiologic examination of the chest and abdomen was unremarkable, and the UVC tip was noted to be positioned in the RA. Despite resuscitative efforts, the patient expired shortly after the event and underwent complete autopsy to determine the cause of death. Autopsy revealed a distended pericardial sac filled with 8 ml of milky-white fluid. Chemical analysis of the fluid revealed a triglyceride level of 777 mg/ dl, consistent with TPN intralipid. Unfortunately, the CVC was removed prior to transfer to the autopsy suite. On gross examination, the RA wall was diffusely discolored and appeared milky-tan. There was no perforation identified and no grossly identifiable lesions. Microscopic examination of the entirely submitted RA showed moderate interstitial edema, predominantly in a subendothelial location, and dilated fine vascular channels in the epicardial soft tissue. No ischemic changes, myocardial necro-

4 166 Annals of Clinical & Laboratory Science, vol. 43, no. 2, 2013 Table 1. Cardiac Tamponade in Neonates: Clinical Features Number of Cases 5 Gender 3 Males, 2 Females Gestational Age at Birth (range): 22 to 41 weeks Gestational Age Less < 27 Weeks 4 of 5 (range 22 to 26-4/7 weeks) Birth Weight 580 to 3,142 GMs Birth Weight 830 GMs 4 of 5 (range 580 to 830 GMs) Weight at Demise 671 to 5,280 GMs Weight 860 GMs 4 of 5 (range 671 to 860 Gm) Age at Demise 4 to 29 Days Fetal-Maternal Complications Chorioamnionitis 2/5 Placenta Previa with Preterm Labor 1/5 Footling Breach 1/5 Preterm Labor with Breach 1/5 Left Diaphragmatic Hernia 1/5 Uterine Leiomyomata 1/5 Central Venous Catheter Type Umbilical Venous Catheter (UVC) 3/5 Umbilical Venous replaced with Peripherally 2/5 Inserted Central Catheter (PICC) TPN Administration Duration 3 to 25 Days Clinical Course Sudden Deterioration 4/5 Deterioration Over Several Day Period 1/5 Extracorporeal Mechanical Oxygenation 1/5 Prior to UVC to PICC Placement Sepsis 2/5 E. Coli 1/5 S. Aureus 1/5 Time from Catheter Insertion to Demise 4 to 25 days sis, intramural thrombosis, hemorrhage, or inflammation were seen. Case 5. The patient was a 29 day-old male neonate with a left diaphragmatic hernia who was born at 41 weeks GA to an 18 year-old G3P1AB1 mother. The mother had a history of sickle cell trait. The birth weight was 3,142 grams. The Apgar scores were 1, 4, and 5 at 1, 5, and 10 minutes, respectively. The patient was intubated due to respiratory distress. UAC and UVC were inserted, and TPN was begun on the third day of life. One week after birth, the left diaphragmatic hernia was surgically repaired. Over the next 3 weeks, the patient had a complicated clinical course, which included trials of ECMO (extracorporeal mechanical oxygenation). About 1 week prior to demise, the patient s condition improved, and he tolerated withdrawal from ECMO support. The UVC line malfunctioned and was replaced with a PICC line. Shortly after, the patient suddenly developed acute bradycardia associated with an enlarged cardiac silhouette. Pericardiocentesis yielded fluid. Despite resuscitation efforts, the patient expired and underwent complete autopsy to determine the cause of death. Autopsy revealed 1 to 2 ml of residual milky-white fluid remaining in the pericardial sac, indicative of a partially successful pericardiocentesis evacuation during resuscitation. The CVC tip was noted to be firmly lodged in the RA wall. Introduction of dye into the distal port of the catheter demonstrated passage though the CVC tip, then through the thin RA wall into the pericardial sac space, consistent with RA wall microperforation. Microscopic examination of the entirely submitted RA at the site of the CVC tip showed marked thinning of the wall to essentially a few cells in thickness. Other histopathologic findings included areas of recent mural organizing thrombus, hemorrhage, focal collagen deposition, subjacent fibrosis,

5 Pericardial Effusion and Cardiac Tamponade in Neonates 167 Table 2. Cardiac Tamponade: Findings at Autopsy Position of Central Venous Catheter Close Contact with Right Atrial Wall 3/5 Proximal to Right Atrium 1/5 Right Atrium by Radiographic Examination 1/5 Pericardial Effusion Milky White Fluid 5/5 Volume Range 2 to 8mL Gross Examination of Right Atrium Right Atrium Intact, But Thin Wall 4/5 Right Atrium Microperforation 1/5 Dye/Saline Infusion via Central Venous Catheter No Leakage Into Pericardial Sac 4/5 Leakage Into Pericardial Sac 1/5 Triglyceride Content of Pericardial Effusion (n=3) 717 to 777 mg/dl Microscopic Features Interstitial Edema 4/5 Dilated Lymphatics 4/5 Myocyte Ischemia 2/5 Fibrinous Thrombus 2/5 Organizing Thrombus 1/5 Fibrinous Epicardial Exudate 1/5 Myocyte Coagulative Necrosis 1/5 and coagulative necrosis of the myocardium in the region corresponding to the CVC tip placement. Myocyte hypertrophy and endocardial thickening were also noted. Results This autopsy series reports five cases of neonatal PCE/CT related to CVC use. The clinical features and findings at autopsy are summarized in Tables 1 and 2 respectively. The 5 neonates ranged in age from 4 to 29 days, and included 3 males and 2 females. The birth weights range from 580 to 3,142 grams. This series included four VLBWNs born at weeks GA and term neonate born at 41 weeks GA. Two patients had positive bacterial blood cultures (Cases 1,3) and were appropriately treated with antibiotics. The infections resolved before occurrence of the fatal event. The time from the CVC insertion to death ranged from 4-29 days. The duration of TPN administration ranged from 3-25 days. All of the patients expired from sudden unexpected cardiac arrest despite aggressive resuscitative efforts. Only a single neonate was suspected of having cardiac tamponade and underwent pericardiocentesis (Case 5). All neonates underwent complete autopsies to determine the cause of death. In all cases at autopsy, milky-white fluid was present within the pericardial sacs (Figure 1). The PCE filled and distended the pericardial sac in Cases 1-4. Pericardiocentesis was performed in Case 5 with only 1-2 ml of residual milky-white PCE present. Chemical analysis of the PCE was performed in 3 cases (Cases 2-4) and showed high triglyceride levels (717 to 777 mg/ dl), consistent with the intralipid component of the TPN. The CVC tips were located proximal to the RA in one case (Case 3) and within the RA in 4 cases (Cases 1, 2, 4, 5). The tip was tightly lodged into the RA of the term neonate (Case 5). Saline or dye infusion through the CVC to test the integrity of the RA was performed in 3 cases (Cases 1, 2, 5, Figure 1). No leakage was noted with the VLBWNs (Cases 1, 2). In contrast, extrusion of the dye through the RA, consistent with microperforation, was demonstrated in the term neonate (Case 5, Figures 1, 2). Gross examination of the RA with the four VLBWN cases (Cases 1-4) revealed intact RA walls. The RA of the term infant (Case 5) was markedly thinned

6 168 Annals of Clinical & Laboratory Science, vol. 43, no. 2, 2013 hemorrhage, foci of collagen deposits, myocyte hypertrophy, and endocardial thickening. These findings were consistent with direct myocardial damage and microperforation caused by the CVC tip. Discussion in the region of catheter placement. All of the RA walls were carefully dissected, and were completely and sequentially submitted for microscopic examination. Microscopic findings of the RAs from the four VLBWNs (Cases 1-4, Figure 2) included interstitial edema and dilated thin walled channels in the epicardial soft tissue (n=4), minute early intramural thrombus (n=1), focal minute fibrinous material on the epicardium (n=1), and small areas with moderate ischemic changes (n=1). No myocardial necrosis, hemorrhage, collagen deposition, myocardial hypertrophy, or acute or chronic inflammation were noted in any of these cases, and the endocardial lining was intact. In contrast, microscopic examination of the RA of the term neonate (Case 5) showed focal coagulative myocardial necrosis, a recent large intramural organizing thrombus and We report five neonates with PCE/CT related to CVC use for which complete autopsy examination was performed in each case. In all cases, the patients presented with sudden cardiac arrest due to milky-white PCE inducing CT. The gross appearance and chemical evaluation with high triglyceride levels (717 to 777 ml) of the PCE were consistent with the intralipid component of TPN administered via the CVCs. The time between CVC insertion and cardiac arrest in VLBWNs is similar in our cases (range: 4-18 days) to that reported in the literature (median: 3 days, range: 0-37 days)[20]. In the term neonate with a left diaphragmatic hernia (Case 5), the fatal event occurred shortly after replacement of the UVC catheter with a PICC line (29 days after initial UVC insertion). Although two patients had a history of bacterial infection during their early hospital course (Cases 1,3), they were treated appropriately with antibiotics. All evidence of infection had resolved in both of these cases at the time of cardiac arrest and at autopsy. Figure 1. Pericardial Effusion and Cardiac Tamponade: Gross Examination Features. (A) Pericardial Sac Markedly Distended by Milky White Fluid; (B) Pericardial Effusion Removed from Pericardial Sac at Autopsy and Submitted for Triglyceride Content Evaluation; (C) Gentle Dye Infusion Through Central Venous Catheter in Right Atrium with Permeation of Right Atrial Wall by Dye (arrow); (D) Tip of Central Venous Catheter Firmly Lodged in Right Atrial Wall with Dye Permeation and Extravasation Through Right Atrial Wall (arrow).

7 Pericardial Effusion and Cardiac Tamponade in Neonates 169 Figure 2. Pericardial Effusion and Cardiac Tamponade: Histopathologic Features. (A) Massive Amount of Dye (arrow) Readily Identified Within Epicardial Tissue and Dissecting Through Interstitium Between Myocardiocytes (arrows, H&E stain); (B & C) Interstitial Edema (arrow, B) and Markedly Dilated, Fine Vascular Channels (arrow, C) in Epicardial Soft Tissue in Representative Right Atria (H&E stain); (D) Early Fibrin Thrombus (T) with Intermixed Erythrocytes and Focus of Underlying Ischemic Myocardiocytes (arrow, H&E stain). The clinical circumstances for all neonates were similar in that they were receiving TPN via CVC when sudden onset of CT secondary to lipemic PCE occurred. However, the mechanism of PCE/ CT in the VLBWN neonates (Cases 1-4) appears to be distinct from that of the term neonate (Case 5). Case 5 was a term neonate with a left diaphragmatic hernia who had a CVC placed secondary to a complicated clinical course. Sudden cardiac arrest occurred shortly after insertion of a replacement central venous line. The CVC tip was found to be firmly lodged into the markedly thinned RA wall. Postmortem dye infusion via the CVC showed leakage through the RA, indicative of microperforation (Figures 1, 2). Microscopic examination revealed evidence of myocardial injury at the CVC tip site, similar to cases reported in the literature [18-20, 23]. In contrast, the four VLBWN neonates (cases 1-4) had different histopathologic findings from the full-term neonate (case 5) and the previously reported cases. In all four VLBWN neonates, TPN was given routinely via CVCs per recommended protocols. Autopsy examination of the neonates hearts demonstrated grossly intact RA walls, and further confirmed by saline/dye infusion via the CVCs. The RA walls were carefully dissected and completely and sequentially submitted for microscopic examination. It is not unexpected that no direct myocardial damage was identified microscopically in Case 3, given that the catheter tip in this case was located proximal to the RA. It is somewhat surprising that there was no evidence of direct myocardial damage in the remaining three VLBWN cases (Cases 1,2, 4), in which the CVC tips were located within the RA. Microscopic findings in

8 170 Annals of Clinical & Laboratory Science, vol. 43, no. 2, 2013 these cases included interstitial edema and dilated fine vascular channels in the epicardial soft tissue (Figure 2). These findings suggest that the PCE/ CT developed as a result of myocardial wall permeation by hyperosmotic TPN contents with intralipid infusion, and probable submicroscopic injury to the endothelium and/or endocardial lining. PCE/CT in infants with appropriate CVC tip positioning have been reported [5, 17-19, 22]. However, no autopsy or histopathologic examinations were performed in these cases. This is the first case series reporting the histopathology of CVC-related PCE/ CT, including a case with appropriate tip positioning. This is also the second report of PCE/CTrelated CVC use which includes cases with no identifiable gross or microscopic myocardial damage. Only one case report in 1993 showed RA histopathologic findings with PCE/CT related to CVC [22]. The CVC tip was coiled in the RA and repositioned to the superior vena cava shortly before death. In this case, the PCE was comprised of serous fluid, and not milky fluid as seen with the current case series. Interstitial and pericardial edema and dilated lymphatics without evidence of atrial perforation were reported. The reported neonate had clinical and histopathologic manifestations of systemic infection, which may have contributed to the development of PCE and CT. The current study raises a concern whether the catheter tip position is of importance in the development of PCE/CT. Several single institution and multicenter studies have been performed utilizing databases or questionnaires [6, 7, 9-11, 23]. These have reported that a considerable proportion of PCE/CT cases had appropriate CVC tip positioning, similar to the findings in the current case series. A Japanese study that included data from 193 NICUs found that most neonatologists preferred to position catheter tips outside of the heart [9]. Only 9% of CVC tips were located within the RA in that study. However, PCE/CT prevalence was not significantly different between the NICUs that allowed CVC tips to be positioned within RAs and those that did not. In summary, this is the first report that describes the right atrial histopathologic findings in cases of PCE/CT related to TPN administration via CVCs. The gross and histopathologic findings may be placed into the following categories: 1) myocardial damage and microperforation associated with mechanical RA injury by direct RA contact with the catheter tip; 2) interstitial edema and dilated fine vascular channels with no histopathologic evidence of direct RA myocardial injury with the catheter tip within the RA; and 3) interstitial edema and dilated fine vascular channels with no histopathologic evidence of direct RA myocardial damage with the catheter tip located outside of the RA. This report presents evidence that: 1) PCE/CT may occur even with appropriate CVC tip positioning; and 2) PCE/CT is most likely associated with permeation of the hyperosmotic TPN contents, in particular intralipid, through the RA wall without gross or microscopic myocardial damage, but evidenced by interstitial edema and dilated fine vascular channels within the epicardial soft tissue. Positioning the catheter tip proximal to the RA may prevent a significant degree of mechanical myocardial damage. However, this still may not prevent permeation of the hyperosmotic TPN contents through the atrial myocardium, resulting in PCE/CT development and subsequent sudden unexpected death. Further studies are necessary to determine the prevalence and etiology of PCE/CT related to CVCs. Further clinical investigations should not be limited to catheter tip positioning alone, but should evaluate other clinical factors. Information such as underlying medical conditions, infections, hypoalbuminemia, TPN duration, CVC types( UVC/UAC vs. PICC), catheter size and material, and catheter tip configuration may prove to be of value. In patients with PICC lines, positional changes in the upper extremity have been postulated to cause migration of the tips [24]. Arm position during radiographic examination should thus be taken into consideration. For instance, the patient in our series with the catheter tip located proximal to the RA (Case 3) had a postmortem radiograph taken with the arm neither abducted nor adducted. If the high osmolality of TPN fluid is indeed a contributory factor in submicroscopic endothelial and endocardial damage leading to TPN and intralipid permeation with resultant PCE/CT additional attention should be directed toward TPN content, osmolality, intralipid, and rate of administration.

9 Pericardial Effusion and Cardiac Tamponade in Neonates 171 Expedient recognition of PCE using echocardiographic, ultrasound, and radiologic examinations may avoid sudden unexpected deaths in neonates. Prior to and at the time of autopsy, it is important for the pathologist to consider PCE/CT in a neonate experiencing sudden unexpected death. Digital photographic documentation of the PCE/ CT and adequate description of the PCE fluid aspirated is important. Submission of the PCE for chemical analysis aids in determination of the role of TPN and intralipid. Prior to disrupting the pericardial sac, infusion of the catheter with dye under gentle pressure is important to replicate the effusion process and evaluate for myocardial leakage and possible microperforation. Documentation of the catheter position at the time of autopsy can be performed by diagnostic imaging, as well as direct visual observation. Gross examination and description of the catheter position and relationship to the right atrium and the myocardium is mandatory. Submission of the entire right atrium for microscopic examination is also necessary. The neonatologist should consider PCE/CT in a neonate with sudden cardiac decompensation. Immediate pericardiocentesis may remove the PCE and avoid sudden death. The neonatologist should be aware of PCE/CT as a potentially fatal TPN complication, and periodically assess the neonate for catheter tip placement and development of the PCE via diagnostic imaging. References 1. Menon G. Neonatal long lines. Arch Dis Child Fetal Neonatal Ed 2003;88(4):F Pettit J. Assessment of infants with peripherally inserted central catheters: Part 1. Detecting the most frequently occurring complications. Adv Neonatal Care 2002;2(6): Mehta S, Connors AF, Jr., Danish EH, Grisoni E. Incidence of thrombosis during central venous catheterization of newborns: a prospective study. 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Pericardial effusion associated with an appropriately placed umbilical venous catheter. J Perinatol 2007;27(5): Onal EE, Saygili A, Koc E, Turkyilmaz C, Okumus N, Atalay Y. Cardiac tamponade in a newborn because of umbilical venous catheterization: is correct position safe? Paediatr Anaesth 2004;14(11): Rogers BB, Berns SD, Maynard EC, Hansen TW. Pericardial tamponade secondary to central venous catheterization and hyperalimentation in a very low birthweight infant. Pediatr Pathol 1990;10(5): Byard RW, Bourne AJ, Moore L, Little KE. Sudden death in early infancy due to delayed cardiac tamponade complicating central venous line insertion and cardiac catheterization. Arch Pathol Lab Med 1992;116(6): Nowlen TT, Rosenthal GL, Johnson GL, Tom DJ, Vargo TA. Pericardial effusion and tamponade in infants with central catheters. Pediatrics 2002;110(1 Pt 1): Stanek J, Willett GD, Lage JM. Idiopathic hydropericardium as a cause of death of a preterm neonate. 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