Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Feasibility of magnetic resonance guided radiotherapy for the treatment of bladder cancer.

Whole bladder magnetic resonance image-guided radiotherapy using the 1.5 Telsa MR-linac is feasible. Full online adaptive planning workflow based on the anatomy seen at each fraction was performed. This was delivered within 45 min. Intra-fraction bladder filling did not compromise target coverage. Patients reported acceptable tolerance of treatment.

Magnetic resonance imaging sequence evaluation of an MR Linac system; early clinical experience.

OBJECTIVES: To systematically identify the preferred magnetic resonance imaging (MRI) sequences following volunteer imaging on a 1.5 Tesla (T) MR-Linear Accelerator (MR Linac) for future protocol development. METHODS: Non-patient volunteers were recruited to a Research and Ethics committee approved prospective MR-only imaging study on a 1.5T MR Linac system. Volunteers attended 1-3 imaging sessions that included a combination of mDixon, T1w, T2w sequences using 2-dimensional (2D) and 3-dimensional (3D) acquisitions. Each sequence was acquired over 2-7 minutes and reviewed by a panel of 3 observers to evaluate image quality using a visual grading analysis based on a 4-point Likert scale. Sequences were acquired and modified iteratively until deemed fit for purpose (online image matching or re-planning) and all observers agreed they were suitable in 3 volunteers. RESULTS: 26 volunteers underwent 31 imaging sessions of six general anatomical regions. Images were acquired in one or two of six general anatomical regions: male pelvis (n = 9), female pelvis (n = 4), chestwall/breast (n = 5), lung/oesophagus (n = 5), abdomen (n = 3) and head and neck (n = 5). Images were acquired using a pre-defined exam-card that on average, included six sequences (range 2-10), with a maximum scan time of approximately one hour. The majority of observers preferred T2-weighted sequences. The thorax teams were the only groups to prefer T1-weighted imaging. CONCLUSIONS: An iterative process identified sequence agreement in all anatomical regions. These sequences will now be evaluated in patient volunteers. ADVANCES IN KNOWLEDGE: This manuscript is the first publication sharing the results of the first systematic selection of MRI sequences for use in on-board MRI-guided radiotherapy by end-users (therapeutic radiographers and clinical oncologists) in healthy volunteers.

Characterization of Porcine Epidemic Diarrhea Virus Isolate US/Iowa/18984/2013 Infection in 1-Day-Old Cesarean-Derived Colostrum-Deprived Piglets.

Porcine epidemic diarrhea virus (PEDV) was first recognized in North America in April 2013 and has since caused devastating disease. The objective of this study was to characterize disease and viral detection associated with an original North American PEDV isolate inoculated in neonatal piglets. Thirty-six 1-day-old cesarean-derived and colostrum-deprived piglets were randomly assigned to the control (n = 16) or challenged group (n = 20); the latter were orogastrically inoculated with 1 ml of US/Iowa/18984/2013 PEDV isolate titered at 1 × 10(3) plaque-forming units per milliliter. Rectal swabs were collected from all piglets prior to inoculation and every 12 hours postinoculation (hpi) thereafter, with 4 control and 5 challenged piglets euthanized at 12, 24, 48, and 72 hpi. One piglet had a positive real-time quantitative polymerase chain reaction test on rectal swab at 12 hpi, and all remaining piglets were positive thereafter, with highest viral quantities detected at 24 and 36 hpi. Diarrhea was evident in 30% and 100% of challenged piglets at 18 and 24 hpi, respectively. Viral antigen was detected in enterocytes by immunohistochemistry in the duodenum and ileum of piglets euthanized at 12 hpi and was apparent throughout the small intestine of all piglets thereafter, with villus height:crypt depth ratios consistently below 4:1. Viremia was confirmed in 18 of 20 pigs at euthanasia. Clinical disease was severe and developed rapidly following infection with an original North American PEDV isolate, with lesions, viremia, and antigen detection possible by 12 hpi.

Shaping up: a geometric morphometric approach to assemblage ecomorphology.

This study adopts an ecomorphological approach to test the utility of body shape as a predictor of niche relationships among a stream fish assemblage of the Tickfaw River (Lake Pontchartrain Basin) in southeastern Louisiana, U.S.A. To examine the potential influence of evolutionary constraints, analyses were performed with and without the influence of phylogeny. Fish assemblages were sampled throughout the year, and ecological data (habitat and tropic guild) and body shape (geometric morphometric) data were collected for each fish specimen. Multivariate analyses were performed to examine relationships and differences between body shape and ecological data. Results indicate that a relationship exists between body shape and trophic guild as well as flow regime, but no significant correlation between body shape and substratum was found. Body shape was a reliable indicator of position within assemblage niche space.

Pathogenesis of porcine epidemic diarrhea virus isolate (US/Iowa/18984/2013) in 3-week-old weaned pigs.

Porcine epidemic diarrhea virus (PEDV) is associated with clinical diarrhea in naïve swine of all ages. This report describes timing of antibody generation and disease progression following infection with a US PEDV isolate by assessing fecal viral shedding, morphometric analysis of intestinal lesions, and magnitude of immunohistochemical staining. Sixty-three, 3-week-old pigs were randomly allocated into control (n=27) and challenged (n=36) groups. Challenged pigs were administered 1 mL of 1 × 10(3) PFU/mL of US/Iowa/18984/2013 PEDV isolate by oro-gastric gavage. Three control and four challenged pigs were necropsied on days post-inoculation (dpi) 1, 2, 3, 4, 7, and weekly thereafter, until study termination on dpi 35. Clinical disease, fecal shedding, body weight, and temperature were monitored during the study period. Diarrhea was observed in challenged pigs beginning for some on dpi 2, affecting a majority of pigs by dpi 6 and subsiding by dpi 10. Average daily gain was significantly lower (P<0.001) for one week post-infection in challenged pigs. PEDV was detected in feces by PCR on dpi 1 and continued in a subset of pigs until dpi 24. PEDV-specific antigen was detected in villous enterocytes of challenged pigs by immunohistochemistry (IHC) on dpi 1, 2, 3, 4, 7, and 14. Microscopic lesions included severe diffuse atrophic enteritis with significantly reduced (P<0.001) villous length observed on dpi 3, 4, and 7. Under the conditions of this study, fecal shedding of PEDV and IHC staining can precede and continue beyond the observation of clinical signs, thus increasing the risk of viral transmission.

Bloodless cardiac surgery and the pediatric patient: a case study.

Peri-operative transfusion of blood or blood products is associated with increased morbidity and mortality after cardiac surgery. However, excessive hemodilution as a result of avoiding the use of homologous blood products can also lead to decreased oxygen delivery to vital end organs and dilutional coagulopathy. This is particularly challenging in pediatric cardiac surgery where there is a large discrepancy between the patient circulating blood volume and the priming volume of the cardiopulmonary bypass (CPB) circuit. Strategies to avoid the use of homologous blood products during pediatric cardiac surgery must also incorporate miniaturization of the CPB circuit and other bypass techniques in order to avoid problems with excessive hemodilution. We report a 5.9 kg male infant who underwent successful surgical correction of a ventricular septal defect without the use of homologous blood transfusion. Our strategies included the pre-operative administration of erythropoietin and iron to increase red blood cell mass, acute normovolemic hemodilution (ANH) before the institution of CPB, retrograde autologous priming (RAP), cell salvage, continuous ultrafiltration, vacuum-assisted venous drainage to minimize the circuit size and priming volume, and the use of near infrared spectroscopy (NIRS) to monitor the patient during the entire procedure. The utilization of these strategies is now standard for our entire pediatric cardiac surgical population.

Hypertriglyceridaemia in Alström's syndrome: causes and associations in 37 cases.

OBJECTIVE: To document frequency of severe hypertriglyceridaemia in Alström's syndrome (AS) and its relationship to hepatic and renal function, glycaemia and insulin resistance. PATIENTS AND METHODS: Thirty-seven subjects with AS aged 5-35 years, 51% male, were assessed at multidisciplinary clinics in Canada, UK and Italy. Diagnostic criteria were: severe cone/rod dystrophy leading to severe visual impairment in early childhood, sensorineural deafness, moderate overall obesity and normal intelligence. Three patients were treated with thyroxine for primary hypothyroidism and one female patient for secondary amenorrhoea with 20 micro g ethinyloestradial combined oral contraceptive. Two male patients were receiving monthly intramuscular testosterone enanthate for secondary hypogonadism. Fasting bloods were taken for serum insulin, serum glucose, serum triglycerides, hepatic and renal function and glycosylated Hb. Triglyceride levels > 8 mmol/l and fasting serum insulin levels > 16 microunits/ml were considered to represent severe hypertriglyceridaemia and severe insulin resistance, respectively. All subjects with (23) hypertriglyceridaemia also had high insulin resistance, as measured by HOMA modelling. However, there was no significant correlation between log tyriglyceride and log serum insulin or HOMA in the whole group (P = 0.2 and 0.14, respectively). There was no clear relationship between serum triglyceride levels and age, body mass index (BMI), hepatic or renal impairment or glycaemia. CONCLUSION: The first overview of serum triglyceride levels in a significant number of reported cases of Alström Syndrome shows an overlap between severe hypertriglyceridaemia and severe hyperinsulinism, but not a direct correlation between the two nor with insulin resistance measured by HOMA. Triglyceride levels were not related to glycaemia, hepatic or renal dysfunction.

Five year results of a prospective very low calorie diet or conventional weight loss programme in type 2 diabetes.

AIMS: To complete 5-year follow-up of an intensive weight loss programme in established type 2 diabetic subjects. METHODS: Forty-five obese type 2 diabetic subjects, Body mass index (BMI) > 30, expressed interest in an intensive weight loss programme. Group 1 comprised 15 who selected very low calorie diet (VLCD), Group 2, 15 selected intensive conventional diet and exercise (ICD), 15 failed to follow either programme. Group sessions of eight to 15 subjects continued weekly for 6 months, then monthly for 12 months with prospective recording at 3, 6 and 12 months and then annually of quality of life, BMI, waist/hip ratio, blood pressure, fasting blood glucose, serum fructosamine and serum lipids. RESULTS: Weight loss was slower in the intensive conventional diet group than in the VLCD group, but better maintained at 5 years: group 1, 4.8 +/- 6 kg; group 2, 8.9 +/- 4 kg. In the intensive conventional diet group, 5 year high-density lipoprotein cholesterol was increased 1.78 +/- 0.26 mmol L-1 vs. 1.10 +/- 0.32 mmol L-1 at baseline, and diastolic blood pressure reduced 74.5 +/- 13.3 vs. 85.5 +/- 13.3 at baseline, both P < 0.05. CONCLUSIONS: Out-patient VLCD treatment proved safe and effective in overweight diabetic subjects but those who chose conventional diet and exercise had a slower but more sustained weight loss. Diabetic patients willing to attempt VLCD may safely lose sufficient weight to allow major surgery, but weight regain is inevitable. Patients willing to undertake a long-term group programme of conventional diet can sustain significant weight loss for 5 years, but still require antidiabetic medication.

The importance of p53-independent apoptosis in the intestinal toxicity induced by raltitrexed (ZD1694, Tomudex): genetic differences between BALB/c and DBA/2 mice.

The thymidylate synthase inhibitor raltitrexed (ZD1694, Tomudex) induces greater intestinal toxicity, manifested as diarrhea and weight loss, in BALB/c than in DBA/2 mice. No convincing pharmacokinetic or pharmacodynamic reason for this strain difference has been established. We have investigated whether this strain difference in response to raltitrexed is related to differential susceptibilities of intestinal mucosae to undergo apoptosis and also whether p53 expression, a critical factor in 5-fluorouracil-induced intestinal apoptosis and toxicity, modulates this response. Ten mg/kg or 100 mg/kg raltitrexed were administered as single or double i.p. injections 24 h apart to BALB/c, DBA/2, and p53-/- mice. Apoptosis, mitosis, and tissue damage were assessed in intestinal epithelium, and animal weight was recorded. BALB/c mice developed diarrhea and weight loss following 100 mg/kg x2 raltitrexed, whereas DBA/2 mice did not. BALB/c mice were more sensitive than DBA/2 to induction of small-intestinal and colonic apoptosis 24 h following 100 mg/kg raltitrexed. Inhibition of mitosis was equivalent in both strains. Both strains showed histopathological damage to the small intestine after 100 mg/kg x2 raltitrexed, but only BALB/c mice demonstrated colonic damage. p53-null mice showed the same level of small intestinal apoptosis as their wild-type counterparts 24 h after 100 mg/kg x1 raltitrexed and also the same levels of intestinal toxicity 3, 5, and 7 days after 100 mg/kg x2 raltitrexed. Thus, BALB/c mice were more susceptible to induction of intestinal apoptosis by raltitrexed than DBA/2 mice and also demonstrated more histopathological damage in the colon correlating with the induction of diarrhea and weight loss. In contrast to 5-fluorouracil, the intestinal apoptosis and toxicity induced by raltitrexed were p53-independent.

Three-dimensional measurement of cerebral microvascular plasma perfusion, glial fibrillary acidic protein and microtubule associated protein-2 immunoreactivity after embolic stroke in rats: a double fluorescent labeled laser-scanning confocal microscopic study.

Early astroglial response to post-ischemic microvascular hypoperfusion may contribute to progressive cerebral microcirculatory impairment and ischemic neuronal injury. Using laser-scanning confocal microscopy and three fluorescent probes, we measured in three-dimensions cerebral microvascular plasma perfusion, astrocytic reactivity, and neuronal injury assessed by fluorescein isothiocyanate (FITC)-dextran, GFAP immunoreactivity, and microtubule associated protein-2 (MAP2) immunoreactivity, respectively, in rats subjected to 2 h of middle cerebral artery occlusion. Three-dimensional quantitative analysis revealed that 2 h of embolic ischemia resulted in a significant (P<0.05) reduction of cerebral microvascular plasma perfusion in the ipsilateral cortex and subcortex. Tissue within the ipsilateral cortex and subcortex with low plasma perfusion exhibited a significant (P<0.05) increase in GFAP immunoreactivity compared with the homologous contralateral tissue. Three-dimensional re-constructed images showed that prominent GFAP immunoreactive astrocytes surrounded large vessels with decreased plasma perfusion in downstream capillaries in the ipsilateral MCA territory when compared to the vessels in the contralateral homologous tissue. Triple fluorescence probe-stained sections showed that tissue with decreased plasma perfusion and with increased GFAP immunoreactivity was accompanied by a reduction of MAP2 immunoreactivity. The present study demonstrates that an impairment of microvascular perfusion induces an early increase in GFAP immunoreactivity, and reactive astrocytes may contribute to a further reduction of cerebral microvascular plasma perfusion. The three-dimensional quantitative imaging analysis used in the present study provides a means to investigate parenchymal cellular responses to changes of cerebral microvascular plasma perfusion after MCA occlusion.

Use of rapid-deployment extracorporeal membrane oxygenation for the resuscitation of pediatric patients with heart disease after cardiac arrest.

INTRODUCTION: We have recently used extracorporeal membrane oxygenation as a means of rapidly resuscitating pediatric patients with heart disease after cardiopulmonary arrest, in whom conventional resuscitation measures have failed. METHODS: We developed a fully portable extracorporeal membrane oxygenation circuit that is maintained vacuum and carbon dioxide-primed at all times. When needed, the circuit is crystalloid-primed and can be ready for use within 15 minutes. Since February 1996, we have used this rapid-deployment circuit to resuscitate 11 pediatric patients in full cardiopulmonary arrest. RESULTS: The median age of the 11 patients was 120 days (2 days to 4.6 years). Nine patients had a cardiac arrest after cardiac surgery. One patient had a cardiac arrest during cardiac catheterization and one patient had a cardiac arrest before cardiac surgery. Median duration of cardiopulmonary resuscitation was 55 minutes (range 20 to 103 minutes), with no difference in the duration of cardiopulmonary resuscitation between survivors and nonsurvivors. Ten of 11 patients (91%) were weaned from extracorporeal membrane oxygenation and seven (64%) survived to hospital discharge. Six patients are long-term survivors, five of whom are in New York Heart Association class I; one survivor is in class II. Seven patients resuscitated with extracorporeal membrane oxygenation before the use of this rapid-deployment circuit had a median duration of cardiopulmonary resuscitation of 90 minutes, with two (28.6%) survivors. CONCLUSIONS: The use of rapid-deployment extracorporeal membrane oxygenation results in shorter resuscitation times and improved survival in pediatric patients with heart disease after cardiopulmonary arrest.

An intensive weight loss programme in established type 2 diabetes and controls: effects on weight and atherosclerosis risk factors at 1 year.

The efficacy, safety, and effect on cardiovascular risk factors of two intensive weight loss programmes in overweight Type 2 diabetic subjects were studied. The patients were recruited from hospital diabetic clinics and control obese subjects from the community. Obese (BMI >30) patients with Type 2 diabetes mellitus and controls were offered intensive conventional diabetic advice or a very low calorie diet. Weekly 2 h sessions were conducted in two day-room areas of adjacent medical wards of Torbay Hospital. Non-diabetic and diabetic very low calorie diet groups reduced BMI by 6 and 5 kg m(-2), respectively, at 1 year. Waist-hip ratios (-0.06 and -0.05) were also reduced (p = 0.04 and p = 0.01), while HDL/total cholesterol ratios increased (+0.04 and +0.06, p = <0.01). Transient changes in blood pressure and antioxidant vitamin status occurred in the intensive conventional diet group. Fourteen of diabetic very low calorie diet subjects discontinued insulin and oral hypoglycaemic agents for the whole year, and psychological well-being transiently improved. Substantial weight loss and improvement in cardiovascular risk factors could be maintained for 1 year in Type 2 diabetic patients by the use of a very low calorie diet.

The relationship between hyaluronidase activity and hyaluronic acid concentration in sera from normal controls and from patients with disseminated neoplasm.

Serum hyaluronidase activity (HAE) and hyaluronic acid (HA) concentration were measured in sera from patients with disseminated neoplasm and compared to those of normal controls. The serum HAE activity in disseminated neoplasm (mean, 12.6 mumol N-acetylglucosamine (NAG)/min/1; range, 5.2-24.7 mumol NAG/min/1) was significantly lower (t = 6.7, p < 0.001) than in normal controls (mean, 17.1 mumol NAG/min/1; range, 11.5-27.0 mumol NAG/min/1). The serum HA concentration in patients with disseminated neoplasm (mean, 8199.7 micrograms/l; range, 42.0-496,000 micrograms/l) was significantly higher (t = 2.63, 0.01 > p> 0.001) than in normal age-matched controls (mean, 55.6 micrograms/l; range, 10.0-348.0 micrograms/l). A negative correlation was found between the serum HAE activity and the HA concentration (r = -0.45, t = 5.92, p < 0.001). The possible reasons for the low serum HAE activity and the raised serum HA concentration in patients with disseminated neoplasm and the negative correlation between the results are discussed.

ECMO in evolution: the impact of changing patient demographics and alternative therapies on ECMO.

The incidence of neonatal extracorporeal membrane oxygenation (ECMO) is decreasing nationally. This decrease is presumed to be a result of the emergence of alternative technologies such as high-frequency oscillatory ventilation (HFOV), nitric oxide (NO), and surfactant therapy as well as others. The purposes of the present report were to determine just how rapidly the demographics of ECMO are changing and to determine the impact of competing technologies on ECMO use. The authors reviewed their entire ECMO experience of 455 cases (370 neonatal, 38 pediatric, and 47 cardiac). The neonatal cases also were separated into diagnostic groups: MAS (meconium aspiration syndrome), PPHN (persistent pulmonary hypertension of the newborn), RDS (respiratory distress syndrome), and sepsis. To allow statistical comparison, the patients were divided into four chronological groups, of equal 3-year duration, spanning the 12 years that ECMO has been available. The results of the analysis demonstrated four principle findings. (1) The total number of patients receiving ECMO per year was declining (P = .0001). This decline was attributable to a reduction in the total number of neonatal patients, with the exception of cases of congenital diaphragmatic hernia. (2) The complexity of each ECMO run was increasing, as evidenced by substantial increases in mean ECMO duration per patient and an increase in the incidence of patient complications on ECMO (P = .0001). (3) There has been a significant decrease in the overall survival rate for patients treated with ECMO (P = .0001). (4) The ECMO population mix has shifted away from straightforward neonatal cases and toward the more complex pediatric and cardiac cases. This demographic shift has occurred as a result of improvements in pre-ECMO management of neonatal patients, and is primarily responsible for the findings noted above. However, there also has been a worsening of condition severity within each diagnostic group, which also is partly responsible for the changes noted. If these trends continue, pediatric, cardiac, and CDH patients will likely account for the majority of ECMO patients. Consequently, existing ECMO centers must be prepared to adapt to the changing demographics by evolving programs that support pediatric, cardiac, and adult patients, in addition to neonates. Furthermore, the complexity associated with transporting these unstable older patients and the likelihood that the number of active ECMO centers will decline may require remaining ECMO centers to develop long-distance ECMO transport capabilities.

Measurement of hyaluronidase activity in normal human serum.

A detailed evaluation of the assay for serum hyaluronidase (HAE) activity originally developed by Bonner and Cantey [W.M. Bonner, Jr. and E.Y. Cantey, Clin. Chim. Acta, 13 (1966) 746-752] is described, together with studies of its precision. The method is based on the liberation of saccharides with N-acetylglucosamine (NAG) end-groups from hyaluronic acid. The NAG is quantitated by heating with alkaline tetraborate to form an intermediate which reacts with p-dimethylaminobenzaldehyde in acidic medium to form a coloured product. The optimised assay, which requires less that 50 microliters of serum, was used to study the HAE activity of 70 normal sera. The mean HAE activity was 17.1 mumol NAG min-1 l-1 (range 11.5-27.0 mumol NAG min-1 l-1); there was no significant difference with age (t = 1.65, 0.5 > P > 0.1) or sex (t = 0.33, P > 0.5).

Resection of a massive sacrococcygeal teratoma using hypothermic hypoperfusion: a novel use of extracorporeal membrane oxygenation.

A 33-week-gestation infant with a massive sacrococcygeal teratoma weighted 4,000 g, but the actual weight of the infant was approximately 1,500 g. With the potential for massive blood loss and impaired lung compliance during resection, some type of cardiopulmonary support was necessary. Resection was undertaken with the assistance of venoarterial extracorporeal membrane oxygenation (ECMO) and hypothermic hypoperfusion. Immediately after removal of the tumor, which weighted 2,420 g, the infant was decannulated from ECMO, and the carotid artery was primarily reconstructed end-to-end. The amount of intraoperative blood loss was 550 mL Postoperatively, the child weighted 1,580 g. Follow-up head ultrasound results were normal, and the patient has done well. This is the first reported case in which ECMO with hypothermic hypoperfusion was used for resection of a massive tumor. This experience shows that ECMO is both useful and safe as a means of temporary cardiopulmonary support for resection of massive tumors in infants.

Coagulation factor deficiencies during initiation of extracorporeal membrane oxygenation.

OBJECTIVE: We examined the hypothesis that critically ill patients receiving extracorporeal membrane oxygenation (ECMO) have reduced clotting factor levels, which may contribute to the risk of hemorrhagic complications. METHODS: Blood samples were collected from 19 patients before and 1 hour after initiation of ECMO. Heparin present in samples was removed by ECTEOLA (epichlorohydrin triethanolamine) cellulose resin adsorption, and coagulation factors were assayed by automated techniques. Factor deficiency was defined as levels at least 2 SD less than published age-adjusted reference values. RESULTS: Thirteen patients (68%) had deficiencies of two or more factors before ECMO. Despite inclusion of factor-containing blood products in the ECMO priming solution, 10 patients (53%) had deficiencies of two or more factors after initiation of ECMO. Four patients had intracranial hemorrhages and were found to be deficient in five or more factors at the time of cannulation. CONCLUSIONS: Severe coagulation factor deficiencies are often present in patients requiring ECMO, and coagulation factors provided through the circuit prime are insufficient to ensure correction of these deficiencies. Deficiency of multiple coagulation factors may contribute to the risk of intracranial hemorrhage during ECMO; the practice of excluding factor-containing solutions from the circuit prime should be examined prospectively.

Respiratory deadspace measurements in neonates with congenital diaphragmatic hernia.

OBJECTIVE: To apply the technique of respiratory deadspace measurement to consecutive infants with congenital diaphragmatic hernia, who were referred to our institution, in order to assess the efficiency of gas exchange. DESIGN: A cohort study evaluating the utility of deadspace measurements in neonates with congenital diaphragmatic hernia. SETTING: Tertiary care pediatric intensive care unit in a university hospital. PATIENTS: Thirty infants with congenital diaphragmatic hernia were studied on presentation to our institution, either before the institution of extracorporeal membrane oxygenation (ECMO) or after stabilization on ECMO. METHODS: The CO2 concentration of expired gas sampled at the exhaust port of the test ventilator was continuously measured and transformed to mixed expired CO2 by the following formula that corrects for compressible volume measured by the ventilatory pneumotachometer: mixed expired CO2 = (PCO2 in exhaust gas) x (ventilatory pneumotachometer minute volume)/(minute volume at the proximal airway). We then utilized the Bohr-Enghoff method to calculate the deadspace/tidal volume ratio: deadspace/tidal volume ratio = (PaCO2 - mixed expired PCO2)/PaCO2. MEASUREMENTS AND MAIN RESULTS: Deadspace/tidal volume ratio was calculated either before the institution of ECMO or during temporary separation from ECMO support as the patients demonstrated improvements in gas exchange and lung compliance. One hundred two measurements were made in 30 patients, with a mean of four measurements per patient (range 1 to 10). There was a significant (p = .005) difference between the first deadspace/tidal volume ratio measured, in survivors vs. nonsurvivors. The mean of the highest deadspace/tidal volume ratio in survivors was 0.47 compared with 0.62 in nonsurvivors (p = .003). A deadspace/tidal volume ratio of > or = 0.60 predicted mortality, with a positive predictive value of 80%, a negative predictive value of 79%, and an odds ratio of 15. The mean pre-ECMO deadspace/tidal volume ratio in those infants who ultimately required ECMO was significantly greater than the mean value for infants not requiring ECMO (0.65 vs. 0.43; p = .004). In patients who were treated with ECMO, survivors demonstrated a significant decrease in deadspace/tidal volume ratio during the course of ECMO. This decrease was not seen in the ECMO-treated patients who did not survive. CONCLUSIONS: Predictors of outcome in infants with congenital diaphragmatic hernia have been complicated and contradictory, particularly in the ECMO era. We demonstrated that the respiratory deadspace can be easily quantified in these infants, and that a physiologic deadspace of > 0.60 is associated with a 15-fold increase in mortality rate. We also demonstrated that in those infants treated with ECMO, the survivors manifested a significant decrease in their deadspace/tidal volume ratio before ECMO decannulation.