Placental Support Research Articles

Angiogenic Factor Imbalance Early in Pregnancy Predicts Adverse Outcomes in Patients With Lupus and Antiphospholipid Antibodies: Results of the PROMISSE Study

(Am J Obstet Gynecol. 2016;214:108.e1–e.14) Systemic lupus erythematosus (SLE) predominantly affects women and commonly presents during their childbearing years. Pregnancy in patients with SLE, particularly those with antiphospholipid (APL) antibodies, and in patients with APL alone, is associated with an increased risk for maternal and fetal morbidity due to preeclampsia (PE) and insufficient placental support of the developing fetus. PE and placental insufficiency are, in turn, associated with adverse pregnancy outcomes (APOs), including maternal complications of PE, intrauterine fetal death, and fetal growth restriction, as well as indicated preterm delivery. Hence the ability to identify patients who are destined for poor outcomes, early in pregnancy, would significantly impact care of this high-risk population.

Fetal intrapericardial teratoma: natural history and management including successful in utero surgery

Intrapericardial teratoma is a rare, lethal tumor often detected in fetal life. Tumor mass and pericardial effusion cause cardiac tamponade that, if relieved, could be life-saving. Optimal timing of intervention and methods for effective fetal treatment are unknown. We describe our single-center experience with fetal intrapericardial teratoma including the first report of successful in utero surgical resection with survival to term. We reviewed our database for suspected fetal intrapericardial teratoma. On fetal ultrasound and echocardiography tumor size was estimated by calculation of an ellipse and analyzed in relation to Doppler-derived fetal cardiac output, venous flow patterns, hydrops, and outcome. Eight fetuses with suspected intrapericardial teratoma were seen from 2009 through 2015. Gestational age at initial presentation ranged from 21-34 (median 26) weeks. Two cases mimicked the appearance of intrapericardial teratoma, but had no serial change in cardiac output over time and were ultimately determined to be other types of tumor. In 6 cases of true intrapericardial teratoma, tumor growth was extremely rapid and associated with progressive decline in cardiac output (to <400 mL/kg/min) manifesting in hydrops and death if left untreated. One case was treated successfully at 31 weeks through ex utero intrapartum delivery with tumor resection while on placental support. Another case underwent open fetal surgery and resection at 24 weeks, with resumption of gestation until delivery at 37 weeks with excellent outcome. Fetal intrapericardial teratoma can be successfully managed utilizing serial surveillance and by treatment in a timely manner prior to the predictable onset of hydrops, determined through increasing tumor size and a declining cardiac output. Surgical resection in utero is possible, with good results.

Ex-utero intrapartum treatment as a novel bridging strategy to surgery in hypoplastic left heart syndrome with intact atrial septum—cross-circulation revisited

Hypoplastic left heart syndromewith an intact or nearly intact septum (HLHS-IS/NIS) constitutes 6%-20% of hypoplastic left heart syndrome cases and represents themost severe form of the disease. Unless there is a pathway for pulmonary venous decompression, hemodynamic instability and death ensue within minutes to hours after birth. Survival depends upon emergent relief of this obstruction, either by operative or interventional techniques. The optimal strategy to bridge a newborn to a stable circulation remains undefined. We describe a novel EXIT (ex-utero intrapartum treatment) strategy using maternal-placental support to bridge a fetus with HLHS-IS/NIS to palliative intervention. A 26-year-old mother was referred for a fetal echocardiogram (at 30 weeks gestation), and the diagnosis of HLHSIS/NIS (with aortic atresia, mitral stenosis) was confirmed (Figure 1, A). The family elected to proceed with fetal intervention, which was performed (at 31 weeks) in another institution. This intervention was complicated by interatrial stent malposition with no demonstrable flow across the septum, and pleural effusion (Figure 1, B). As delivery neared, the parents requested aggressive management. Although our usual approach at birth is immediate catheter intervention, this strategy would be complicated by the oblique stent position in the right atrium. An EXIT to achieve cardiopulmonary bypass (CPB) was proposed to allow the fetus to remain on placental support while undergoing median sternotomy and initiation of CPB. The strategy was the consensus from a multidisciplinary fetal care conference as the safest means of maintaining hemodynamic stability before establishing interatrial communication. After the mother suffered premature rupture of membranes, a multidisciplinary team was mobilized for an emergent EXIT procedure. General anesthesia was induced using

Sustained inflation at birth did not alter lung injury from mechanical ventilation in surfactant-treated fetal lambs.

BackgroundSustained inflations (SI) are used with the initiation of ventilation at birth to rapidly recruit functional residual capacity and may decrease lung injury and the need for mechanical ventilation in preterm infants. However, a 20 second SI in surfactant-deficient preterm lambs caused an acute phase injury response without decreasing lung injury from subsequent mechanical ventilation.HypothesisA 20 second SI at birth will decrease lung injury from mechanical ventilation in surfactant-treated preterm fetal lambs.MethodsThe head and chest of fetal sheep at 126±1 day GA were exteriorized, with tracheostomy and removal of fetal lung fluid prior to treatment with surfactant (300 mg in 15 ml saline). Fetal lambs were randomized to one of four 15 minute interventions: 1) PEEP 8 cmH2O; 2) 20 sec SI at 40 cmH2O, then PEEP 8 cmH2O; 3) mechanical ventilation with 7 ml/kg tidal volume; or 4) 20 sec SI then mechanical ventilation at 7 ml/kg. Fetal lambs remained on placental support for the intervention and for 30 min after the intervention.ResultsSI recruited a mean volume of 6.8±0.8 mL/kg. SI did not alter respiratory physiology during mechanical ventilation. Heat shock protein (HSP) 70, HSP60, and total protein in lung fluid similarly increased in both ventilation groups. Modest pro-inflammatory cytokine and acute phase responses, with or without SI, were similar with ventilation. SI alone did not increase markers of injury.ConclusionIn surfactant treated fetal lambs, a 20 sec SI did not alter ventilation physiology or markers of lung injury from mechanical ventilation.

Optimizing Outcome: Use of a Checklist for Otolaryngologists Overseeing Ex Utero Intrapartum Treatment (EXIT)

Objectives: Evaluate elements necessary in the decision making and execution during ex-utero intrapartum treatment (EXIT) and operation on placental support (OOPS) procedures to ensure superior outcomes. Methods: Retrospective review of neonatal head and neck obstruction cases from January 1998 to January 2013 at two tertiary referral centers. Main outcome measures: Data regarding prenatal care, delivery details, pathology of lesion, and postnatal course. Results: From 1998-2013, 13 of the 15 cases of prenatally-diagnosed potentially severe head and neck obstruction used an EXIT or OOPS procedure to secure the airway. The decision making process leading to whether an EXIT procedure needed to be performed was reviewed. Additionally, we analyzed elements that must be addressed in the checklist, including defined tasks for the specialties of perinatology, neonatology, anesthesia, fetal imaging, pediatric otolaryngology, and operative services to optimize outcome. Equipment and space needs are addressed as well. Multidisciplinary rehearsal of the procedure is strongly recommended, with the pediatric otolaryngologist leading the process. We offer a comprehensive checklist for the otolaryngologist overseeing such procedures. Conclusions: Medical checklists are increasingly being used to ensure safety and improve outcomes in complex patient care situations. Obstructive masses of the head and neck in the fetus present a difficult and potentially fatal clinical problem. Based on our experience, we offer the otolaryngologist a structured and well-choreographed approach in dealing with such complex situations, with the incorporation of a comprehensive checklist for EXIT procedures.

Multidisciplinary perinatal management of the compromised airway on placental support: lessons learned

The aims of this study were to review fetal and maternal outcomes after management of the compromised perinatal airway via operation on placental support or ex utero intrapartum treatment and to discuss implications for future management of these complex and rare cases. We have presented a retrospective case series of 12 neonates requiring airway management on placental support at a single tertiary care, academic center. One mother experienced significant blood loss. Operative recovery times were unremarkable. Eight neonates required airway management due to mass obstruction, two for removal of an endotracheal balloon for fetoscopic treatment of congenital diaphragmatic hernia, one for laryngeal atresia, and one for severe retrognathia. One of our series is an unusual case of management on placental support after vaginal delivery. Another child would have ideally been managed on placental support, but an extremely short umbilical cord prevented this. Even though the airway was secured in all 12 cases, five neonates died in the perinatal period. These procedures have a risk for substantial maternal blood loss. Despite excellent rates of success securing the neonatal airway, children who require management on placental support still have high mortality. A formalized multidisciplinary approach at our institution has enhanced preparedness for these cases.

Sustained inflation at birth did not protect preterm fetal sheep from lung injury

Sustained lung inflations (SI) at birth may recruit functional residual capacity (FRC). Clinically, SI increase oxygenation and decrease need for intubation in preterm infants. We tested whether a SI to recruit FRC would decrease lung injury from subsequent ventilation of fetal, preterm lambs. The preterm fetus (128±1 day gestation) was exteriorized from the uterus, a tracheostomy was performed, and fetal lung fluid was removed. While maintaining placental circulation, fetuses were randomized to one of four 15-min interventions: 1) positive end-expiratory pressure (PEEP) 8 cmH2O (n=4), 2) 20 s SI to 50 cmH2O then PEEP 8 cmH2O (n=10), 3) mechanical ventilation at tidal volume (VT) 7 ml/kg (n=13), or 4) 20 s SI then ventilation at VT 7 ml/kg (n=13). Lambs were ventilated with 95% N2/5% CO2 and PEEP 8 cmH2O. Volume recruitment was measured during SI, and fetal tissues were collected after an additional 30 min on placental support. SI achieved a mean FRC recruitment of 15 ml/kg (range 8-27). Fifty percent of final FRC was achieved by 2 s, 65% by 5 s, and 90% by 15 s, demonstrating prolonged SI times are needed to recruit FRC. SI alone released acute-phase proteins into the fetal lung fluid and increased mRNA expression of proinflammatory cytokines and acute-phase response genes in the lung. Mechanical ventilation further increased all markers of lung injury. SI before ventilation, regardless of the volume of FRC recruited, did not alter the acute-phase and proinflammatory responses to mechanical ventilation at birth.

The Multiple Faces of the Decidual Natural Killer Cell

The decidual NK (dNK) cell is called on to support placental growth by providing an array of growth factors that directly transform the spiral artery and direct trophoblast invasion. Successful transformation is dependent upon adequate stimulation paradoxically stimulating the cell for placental support rather than cytotoxicity. With the identification of its supportive role, the presence of an intact cytotoxic mechanism has been confusing. Investigators have found that the cell remains fully capable of cytotoxic responses particularly in response to pathogen-specific signals. We postulate a dual threshold model where moderate stimulation results in release of stimulatory factors supporting placentation while intense stimulation, particularly triggered through pathogen-specific receptors, restores the cell to its protective, cytotoxic, role. Individual dNK cells mature attaining the capacity to respond to the delivery of cognate signals. The process, known as 'licensing' tunes responsiveness to the degree to which stochastically selected inhibitory receptors block cytotoxic response to self. A changing licensing milieu within the decidua may result in altered and unsuitable receptor expression. We postulate that a heterogeneous population of dNK cells where cells inappropriately licensed for the milieu contributes to pathology.

Prenatal diagnosis of fetal cervicofacial anomalies

To review the current literature on prenatal diagnosis of cervicofacial anomalies that may require neonatal intervention or that require prenatal counseling by a maternal-fetal medicine team and otolaryngology, head and neck surgery. Ultrasound and MRI imaging are complementary in the prenatal diagnosis of fetal anomalies that may present with the need for the head and neck surgeon to assist with airway management at delivery or that require prenatal counseling. Team approaches to delivery of at-risk infants have improved and there is more experience with the ex-utero intrapartum treatment (EXIT) procedure. The importance of planning and simulation for EXIT is essential prior to delivery. Future directions include in-utero gene therapy and fetal surgery. Advances in detection and treatment of fetuses at risk for airway obstruction at birth and for accurate diagnosis of facial clefting will allow teams to continue to improve outcomes for these infants. Increased experience of such teams will allow refinement of protocols and indices for decision making regarding which fetuses will need treatment on placental support and which will do well with traditional delivery with treatment teams on standby. This will allow improved risk profiles for both mother and child.

Ex utero intrapartum treatment in the management of giant cervical teratomas

PurposeThe purpose of this study is to present the outcome and technical details of the Ex Utero Intrapartum Treatment (EXIT) procedure performed in the management of the fetus with a giant cervical teratoma. MethodsA retrospective review of the medical records of patients undergoing the EXIT procedure between September 1995 and September 2010 was performed. ResultsEighty-seven EXIT procedures were performed. In 20% of cases (17/87), the indication was giant cervical teratoma. There were 10 females and 7 males. Polyhydramnios was present in 82%. Median gestational age at EXIT was 35 weeks (range, 30-39 weeks). Median birth weight was 2.5 kg (range, 1.7-3.7 kg). Access to the airway under placental support was established in all cases via direct laryngoscopy/bronchoscopy in 8 patients (47%) and via surgical exploration (tracheostomy or retrograde intubation) in 9 patients (53%). The mortality rate under placental support was zero. Seven patients had the tumors resected immediately after the EXIT, 6 patients had the resection later, and 4 patients died before resection. The neonatal mortality rate was 23% (4/17 patients). Patients who died had severe pulmonary hypoplasia that resulted from the upward traction by the giant cervical mass on the airway and compression of the lungs against the thoracic apex. ConclusionsWe conclude that the EXIT procedure continues to be the optimal delivery strategy for patients with prenatally diagnosed giant cervical teratomas and potential airway obstruction at birth. A thorough evaluation of the prenatal images and an experienced multidisciplinary team are key factors for an effective approach to the obstructed fetal airway.

A rare congenital cystic malformation of the oral cavity requiring OOPS (operation on placental support) procedure at delivery

An 18 year old para1+0 was referred to our fetal medicine unit with an intraoral cystic structure (22mm×19mm) detected at routine anomaly scan. Fetal MRI confirmed a large thin walled...

EXIT (Ex utero Intrapartum Treatment) in lymphatic malformations of the head and neck: Discussion of three cases and proposal of an EXIT-TTP (Team Time Procedure) list

Objectives Ex utero Intrapartum Treatment (EXIT) is a technique to secure the fetal airway while oxygenation is maintained through utero-placental circulation. The aim of the study is to present three cases of fetal lymphatic malformation of the head and neck that required EXIT and to summarize EXIT details. Methods The cases were studied before the delivery and EXIT was planned with a multidisciplinary team. The key factors of EXIT are considered and the type, stage and clinical score of the three lymphatic malformations are defined. Results In the three cases of EXIT the time working on placental support to secure the airway was 9, 7, and 9 min, respectively (from the hysterotomy to clamping the umbilical cord). Procedures performed on the airway were laryngo–tracheo–bronchoscopy in the first case, laryngoscopy and intubation in the second one, laryngoscopy, drainage of the lymphatic macro-cyst, and intubation in the third case. A sketching to detail the EXIT steps are presented: EXIT-Team Time Procedure list (EXIT-TTP list). Lymphatic malformations were classified as mixed (micro/macro-cystic) in two cases, and macro-cystic in one. de Serres Stage was IV, V and II. Therapy varied in the three neonates (surgery alone, surgery + Picibanil ® + Nd-YAG, or Picibanil ® alone). Conclusions In case of prenatal suspicion of airway obstruction, EXIT should be planned with a multidisciplinary team. The EXIT-Team Time Procedure list (EXIT-TTP list), reviews the most critical phases of the procedure when different teams are working together. The type of lymphatic malformation, the anatomic location and the clinical score predict the outcome.

Case Scenario: Anesthesia for Maternal-Fetal Surgery

Case Scenario: Anesthesia for Maternal-Fetal Surgery

Ex-utero intrapartum treatment procedure for giant neck masses—fetal and maternal outcomes

Background/PurposeFor fetuses with giant neck masses and tracheal obstruction, an ex-utero intrapartum treatment (EXIT) procedure allows for safe nonemergent airway management while on placental support. Our objective was to examine fetal and maternal outcomes after EXIT procedure specifically for giant neck masses. MethodsThe medical records of all patients referred to a comprehensive fetal center for a giant neck mass between 2001 and 2010 were reviewed retrospectively. ResultsAmong 24 patients referred, an EXIT procedure was performed in 12 with evidence of tracheal compression. An EXIT procedure was not performed because of minimal tracheal involvement (n = 8), elective abortion (n = 2), fetal demise (n = 1), or obstetric complication (n = 1). In all fetuses, the airway was successfully secured; tracheal intubation was achieved with rigid bronchoscopy (n = 10), direct laryngoscopy (n = 1), and tracheostomy (n = 1). Eleven patients survived to discharge, whereas 1 patient with significant pulmonary hypoplasia died 8 days after emergency EXIT procedure. Of 11 surviving infants, 10 are neurodevelopmentally intact. All mothers who desired future pregnancies have subsequently had uncomplicated deliveries (n = 6). ConclusionsEx-utero intrapartum treatment procedure for giant neck mass can be performed safely for both mother and child. Most fetuses can be orotracheally intubated with minimal long-term morbidity. The potential for future pregnancies is preserved.

EXIT Procedure: Technique and Indications with Prenatal Imaging Parameters for Assessment of Airway Patency

Successful management of fetal conditions in which airway obstruction is anticipated is now possible because of advances in prenatal imaging and the development of innovative techniques to secure the fetal airway before complete separation of the fetus from the maternal circulation. Fetal ultrasonography and fetal magnetic resonance imaging are complementary imaging modalities in the assessment of fetuses with potential airway obstruction. The ex utero intrapartum therapy (EXIT) procedure is used to secure the fetal airway before complete delivery of the fetus. However, successful intrapartum treatment of fetuses who may need prolonged placental support depends on a multidisciplinary assessment in which the benefits of the EXIT procedure for the fetus are weighed against the risk of maternal complications that may occur during prolongation of the intrapartum period to secure the fetal airway. This multidisciplinary approach requires an understanding of the types of lesions in which intrapartum fetal airway access would be beneficial, a knowledge of the prenatal images that would best delineate the anatomic defect and thus help guide the best approach to securing the airway, and consensus and coordination among medical ethicists, radiologists, obstetric anesthesiologists and obstetricians, pediatric surgeons and anesthesiologists, and neonatologists.

Comprehensive Airway Management of Neonatal Head and Neck Teratomas

To determine the success of initial airway management and to characterize late airway-related complications in patients with airway obstruction due to congenital head and neck teratomas. Case series with chart review. Tertiary airway referral institution. Review of consecutive patients with congenital head and neck teratomas from 1988 to 2010. Variables examined include initial airway stabilization at time of birth and perinatal airway management. Outcomes include short- and long-term complications. Fourteen cases were reviewed. In 12 patients, initial airway management was accomplished on placental support with either intubation or tracheotomy. Two vaginal births required subsequent uncomplicated oral intubation within 24 hours. Nine patients required tracheotomy (3 within the delivery suite, 2 during mass excision on day of life 6 and 24, and the remaining 4 occurred at days 29, 32, 92, and 100). Five deaths occurred, 4 within several days of birth due to complications related to the cervical teratomas and 1 on day of life 32 due to an airway-related complication. Follow-up for surviving patients ranged from 1 month to 18 years. Long-term airway complications ranged from vocal cord paralysis to stenosis requiring laryngotracheoplasty. This study demonstrates that a multidisciplinary team and a standardized approach in the operating suite have led to successful initial airway stabilization. Furthermore, this study demonstrates the need for continued airway management after delivery. Reassessment of the airway after delivery and an airway management planning meeting with the multidisciplinary team may help decrease morbidity and mortality.

Primate milk: Proximate mechanisms and ultimate perspectives

To understand the evolutionary forces that have shaped primate lactation strategies, it is important to understand the proximate mechanisms of milk synthesis and their ecological and phylogenetic contexts. The lactation strategy of a species has four interrelated dimensions: the frequency and duration of nursing bouts, the period of lactation until weaning, the number and sex ratio of infants that a mother rears simultaneously, and the composition and yield of the milk that mothers synthesize. Milk synthesis, arguably the most physiologically costly component of rearing infants, remains the least studied. Energy transfer becomes energetically less efficient, transitioning from placental support to milk synthesis just as the energy requirements for infant growth, development, and behavioral activity substantially increase. Here we review primate lactation biology and milk synthesis, integrating studies from anthropology, biology, nutrition, animal science, immunology, and biochemistry, to identify the derived and ancestral features of primate milks and enhance our understanding of primate life history.

Inflammation and lung maturation from stretch injury in preterm fetal sheep.

Mechanical ventilation is a risk factor for the development of bronchopulmonary dysplasia in premature infants. Fifteen minutes of high tidal volume (V(T)) ventilation induces inflammatory cytokine expression in small airways and lung parenchyma within 3 h. Our objective was to describe the temporal progression of cytokine and maturation responses to lung injury in fetal sheep exposed to a defined 15-min stretch injury. After maternal anesthesia and hysterotomy, 129-day gestation fetal lambs (n = 7-8/group) had the head and chest exteriorized. Each fetus was intubated, and airway fluid was gently removed. While placental support was maintained, the fetus received ventilation with an escalating V(T) to 15 ml/kg without positive end-expiratory pressure (PEEP) for 15 min using heated, humidified 100% nitrogen. The fetus was then returned to the uterus for 1, 6, or 24 h. Control lambs received a PEEP of 2 cmH(2)O for 15 min. Tissue samples from the lung and systemic organs were evaluated. Stretch injury increased the early response gene Egr-1 and increased expression of pro- and anti-inflammatory cytokines within 1 h. The injury induced granulocyte/macrophage colony-stimulating factor mRNA and matured monocytes to alveolar macrophages by 24 h. The mRNA for the surfactant proteins A, B, and C increased in the lungs by 24 h. The airway epithelium demonstrated dynamic changes in heat shock protein 70 (HSP70) over time. Serum cortisol levels did not increase, and induction of systemic inflammation was minimal. We conclude that a brief period of high V(T) ventilation causes a proinflammatory cascade, a maturation of lung monocytic cells, and an induction of surfactant protein mRNA.

Obstetric hemorrhage during an exit procedure for severe fetal airway obstruction

To report a case of massive obstetric hemorrhage occurring during Cesarean delivery for an ex utero intrapartum treatment (EXIT) procedure. Methods to optimize the anesthetic, obstetric, and perinatal management are discussed. A healthy parturient underwent an urgent EXIT procedure at 32 weeks gestation for a giant fetal neck mass. During the intraoperative period, severe intraoperative hemorrhage occurred from the site of the uterine incision. No evidence of placental bleeding, premature placental separation, or inadequate uterine relaxation was observed during the perioperative period. Placement of a uterine stapling device was unsuccessful in achieving adequate surgical hemostasis. Initial attempts with laryngoscopy and rigid bronchoscopy to secure the fetal airway on placental support were unsuccessful, and early termination of placental support was deemed necessary due to the severity of maternal blood loss. After full delivery of the neonate and termination of placental support, neonatal ventilation with bag-mask ventilation was achieved and successful endotracheal intubation occurred during repeat bronchoscopy. The risk of obstetric hemorrhage due to uterine relaxation and inadequate surgical hemostasis in patients undergoing EXIT procedures is poorly reported. To reduce adverse maternal and neonatal outcomes, the premature termination of placental support during EXIT procedures may be required in the setting of severe obstetric hemorrhage.

Brief, Large Tidal Volume Ventilation Initiates Lung Injury and a Systemic Response in Fetal Sheep

Premature infants are exposed to potentially injurious ventilation in the delivery room. Assessments of lung injury are confounded by effects of subsequent ventilatory support. To evaluate the injury response to a brief period of large tidal volume (Vt) ventilation, simulating neonatal resuscitation in preterm neonates. Preterm lambs (129 d gestation; term is150 d) were ventilated (Vt = 15 ml/kg, no positive end-expiratory pressure) for 15 minutes to simulate delivery room resuscitation, either with the placental circulation intact (fetal resuscitation [ FR]) or after delivery (neonatal resuscitation [NR]). After the initial 15 minutes, lambs received surfactant and were maintained with either ventilatory support (FR-VS and NR-VS) or placental support (FR-PS) for 2 hours, 45 minutes. A control group received no resuscitation and was maintained with placental support. Samples of bronchoalveolar lavage fluid, lung, and liver were analyzed. Inflammatory cells and protein in bronchoalveolar lavage fluid, heat shock protein-70 immunostaining, IL-1beta, IL-6, IL-8, monocyte chemotactic protein-1, serum amyloid A (SAA)-3, Toll-like receptor (TLR)-2, and TLR4 mRNA in the lungs were increased in the FR-PS group compared with control animals. There were further elevations in neutrophils, IL-6, and IL-8 mRNA in the FR-VS and NR-VS groups compared with FR-PS. SAA3, TLR2, and TLR4 mRNA increased in the liver in all resuscitation groups relative to control animals. Ventilation for 15 minutes with a Vt of 15 ml/kg initiates an injurious process in the preterm lung and a hepatic acute-phase response. Subsequent ventilatory support causes further increases in some injury indicators.