Giuseppe A. Marraro

Multicenter, randomized, controlled study of porcine surfactant in severe respiratory syncytial virus-induced respiratory failure*

Objective Recently, natural exogenous surfactant replacement has been used in experimental models and clinical trials for the treatment of severe respiratory syncytial virus (RSV) disease. The present study was aimed at verifying this hypothesis and confirming the results of our previous pilot study by assessing the effect of surfactant treatment in mechanically ventilated infants with severe RSV-induced respiratory failure. Design Multicenter, randomized, controlled study. Setting Six pediatric intensive care units staffed by full-time intensive care physicians. Patients A total of 40 infants (20 treated and 20 controls) with RSV-induced respiratory failure requiring conventional mechanical ventilation (CMV) were randomly assigned to either exogenous surfactant (treated group) or conventional treatment (control group) over a 1-yr period. Interventions Fifty milligrams per kilogram of body weight of porcine-derived natural surfactant (Curosurf) was administered. The drug was instilled by means of a syringe attached to a small suction catheter inserted into the endotracheal tube down to its tip, momentarily disconnecting the patient from CMV. Main Outcome Measures The assessment consisted of the following outcome variables: duration of CMV, length of intensive care unit stay, gas exchange, respiratory mechanics, re-treatment need, complications, and mortality. Results The two groups were similar with regard to demographics, Pediatric Risk of Mortality scores, and baseline Pao2/Fio2, Paco2, and ventilator settings. A marked increase in Pao2/Fio2 and decrease in Paco2 were observed in the treated group after surfactant administration. Hemodynamic parameters remained unchanged throughout the study period. Peak inspiratory pressure and static compliance were similar at baseline in the two groups. A decrease in peak inspiratory pressure and increase in static compliance were observed in the treated group after surfactant administration. Among surfactant-treated patients, 15 received the treatment within 24 hrs of admission, whereas the remainder (five patients) were treated later. Among children who were treated later, three needed an additional dose of surfactant. None of the children treated within 24 hrs needed an additional dose. Duration of CMV and length of stay in the intensive care unit were significantly shorter in the treated group (4.6 ± 0.8 and 6.4 ± 0.9 days, respectively) compared with the control group (5.8 ± 0.7 and 8.2 ± 1.1 days, respectively) (p < .0001). No relevant complications were observed, and all the infants survived. Conclusions Consistent with our previous study and others, this study shows that surfactant therapy improves gas exchange and respiratory mechanics and shortens CMV and intensive care unit stay in infants with severe RSV-induced respiratory failure.

One lung ventilation in infants and children: experience with marraro double lumen tube

Background : Our objective was to evaluate the efficacy of selective bronchial intubation and independent lung ventilation during thoracic surgery in children up to 3 years, using a double lumen tube.

Protective lung strategies during artificial ventilation in children

Since its first use, mechanical ventilation proved to be of great value in reducing mortality of many patients (newborns, infants, children, and adults) affected by severe respiratory failure. However, mechanical ventilation can, in itself, create pulmonary damage (ventilation-induced lung injury, VILI) and also damage to other organs (multiorgan failure, MOF), specifically when high FiO2 is used and inflammation mediators are not controlled. The complications induced by high peak pressures (interstitial emphysema, pneumothorax, pneumomediastium) have been known for many years (1–4). Pressure-controlled ventilation has been proposed and widely used to control intrapulmonary pressures in neonates and infants, but this method has not reduced the incidence of interstitial emphysema and pneumothorax, nor bronchopulmonary dysplasia (BPD), which remains a disabling complication in ventilator-treated newborns and infants (5–7). At present it is common knowledge that the control of high transpulmonary pressures reduces the risk of lung overdistention, but it does not lead to the control of tidal volume, so that the lung is alternatively hypoand hyperventilated depending on variations of airway resistance (e.g. increase in secretions and bronchosuctioning). Such unstable ventilation could lead to unhomogeneous lung pathology and favor the development of BPD. In the mid 1980s the idea of protecting the lung and reexpanding only the nonventilated areas favored the development of independent lung ventilation by means of selective bronchial intubation (8). Although the method was never confirmed by large scale-controlled clinical studies in children, the theory behind its application drew attention, on one hand to the damage that can be caused to the better lung when it is overexpanded to achieve adequate gas exchange and on the other to the necessity to reopen the lung with worse pathology as quickly as possible in order to improve gas exchange, reduce the ventilation/perfusion mismatch and limit trauma to the less damaged lung (9–12). In the 1990s the next step was to focus attention not only on reopening the lung but also on keeping it open during the whole breathing cycle, with the aim of preventing trauma deriving from the pressure required to reopen the terminal bronchiole and overcome the shear forces which can favor the onset of lung damage. The ‘open up the lung and keep the lung open’ concept is the state of the art in ventilation at the present day in adults and pediatrics. It involves the application of methods to open and recruit the lung immediately at the start of artificial ventilation and whenever atelectasis occurs (13,14). Once the lung has been reopened, various techniques can be applied to ensure that it remains open. Correspondence to: Giuseppe A. Marraro MD, Corso Porta Nuova 23 – I 20121 Milano, Italy (email: gmarraro@picu.it). Pediatric Anesthesia 2005 15: 630–637 doi:10.1111/j.1460-9592.2005.01653.x

Selective medicated (normal saline and exogenous surfactant) bronchoalveolar lavage in severe aspiration syndrome in children.

Objective: To study the ability of volume-controlled ventilation and medicated (normal saline plus surfactant) bronchoalveolar lavage in aspiration to reduce the duration of intubation and improve gas exchange. Design: Randomized controlled clinical trial. Setting: Pediatric intensive care unit. Patients: Twenty children, 1 month to 16 yrs old, who were intubated and mechanically ventilated, were randomized within 6 hrs of aspiration to receive volume-controlled ventilation plus medicated bronchoalveolar lavage (treatment group) or the same ventilation and bronchosuction (control group). Interventions: Volume-controlled ventilation and positive end-expiratory pressure (10–12 cm H2O) were applied. Medicated bronchoalveolar lavage was performed using five aliquots of 5 mL of saline plus 10 mg/mL Curosurf (porcine surfactant, Chiesi Pharmaceutical SpA, Parma, Italy) in infants, five boluses of 10 mL of saline plus 5 mg/mL Curosurf in children, and four boluses of 25 mL of saline with 2.4 mg/mL Curosurf in adolescents for each affected lobe. One hour after bronchoalveolar lavage, 240 mg of Curosurf was administered locally. Measurements and Main Results: All patients survived. In the treatment group, days of intubation were 4.6 (±1.07), oxygenation index and Pao2/Fio2 improved significantly at 24 hrs, and statistical reduction in tidal volume mL/kg was observed from 36 hrs. In the control group, days of intubation were 11.8 (±3.22) (p < .0001), no improvement in oxygenation was noted, and pneumonia was observed in seven children (70%). Conclusions: Even though this was an unblinded small clinical trial and low tidal volume strategy was not employed at an early stage after lung injury, there is some evidence that bronchoalveolar lavage with normal saline and surfactant may have clinical value in treating severe aspiration syndrome in children. More clinical studies are warranted to overcome study limitations and potential bias.

Evaluation of the efficiency of heat and moisture exchangers during paediatric anaesthesia

This study evaluates the efficiency of heat and moisture exchangers (HMEs) in allowing adequate humidification and warming during anaesthesia in children. Eighteen paediatric patients undergoing anaesthesia were divided into two groups: group A ten patients: infants up to 10 kg→Hygrobaby HME; group B 8 patients: children above 10 kg→Hygroboy HME. The following parameters were evaluated: body temperature (bT), room temperature (rT), fresh gas temperature, HME warm‐up time, inspired and expired gases temperature and humidity, conserving efficiency, and duration of anaesthesia. Gas temperatures were recorded by means of a recorder fitted with four thermal probes. Humidity values were mathematically derived. The correlation between efficiency and rT, bT, and fresh gas temperature was computed. In both groups the inspired gases temperatures were below 30??C. Inspired absolute humidity was never more than 28 mgH2O??l−1. The conserving efficiency was good (0.93 in both groups). A positive correlation was found between efficiency and fresh gas temperature. HMEs did not meet the minimum standards for humidity and heating during anaesthesia in children, although their conserving efficiency was found to be satisfactory.

Surfactant treatment in the ICU: alternative interpretations of existing evidence

The Adult Respiratory Distress Syndrome (ARDS) – by any definition – was the condition to treat (1) and a long list of papers described successful experimental work following the concept of surfactant administration for the treatment of established ARDS. Unsatisfactorily, there is only a short list of papers describing clinical success; no randomized clinical trial (RCT) with sufficient power among them. In this editorial, we will argue that this situation is the consequence of a series of overdrawn extrapolations and simplifications. For the sake of clarity we will pick three main representative considerations and show how alternative interpretations of evidence may lead to more promising approaches for the use of surfactant in the ICU. The application of surfactant in ARDS is based on biologically plausible evidence and is proven to be highly effective in preterm neonates. At this point, the first overdrawn extrapolation was made; if it is beneficial in preterm babies to administer a high dose of surfactant as a bolus via the trachea, it must work likewise in older patients. Further support to the high-dose bolus concept came from experiments showing that edema fluid (and its components) is able to inhibit and/or degrade natural surfactant present in the lungs. The conclusion was simple: more surfactant to overcome inhibition and to replenish the functionally reduced surfactant. At that time, series of experimental studies were published in support of this way of thinking. The results of these studies were so convincing that the increasing knowledge of the striking pathophysiologic differences between the neonate and the adult situation was neglected. In addition, these studies not only supported the tradition of the high-dose bolus , they were also the starting point for the second overdrawn extrapolation. Virtually, all types and variations of lung injury models in almost every animal used in experimental traumatology responded to pouring down surfactant the trachea and thus, led to the simplified belief that any type of lung injury can be effectively and similarly treated with surfactant. This belief was supported by analytical evidence that every type of lung injury leads to functional and compositional changes of pulmonary surfactant, which in turn aggravate lung injury (2). So what could be more obvious than interrupting this vicious cycle by treatment with surfactant? The third gross simplification is directly linked to the current diagnosis of ARDS. The high mortality and morbidity of ARDS continues to be one of the biggest challenges for intensivists and a main target for therapeutic intervention. Clinical research in intensive care is frequently conducted in large RCTs. Their results are accepted as reliable evidence for the therapeutic efficacy of a treatment by clinicians and influence therapeutic regimes (3). However, planning and conducting RCTs are strongly influenced by definitions and so are their results, which in turn influence the definition of inclusion and exclusion criteria as well as clinical endpoints including mortality (4). The currently used definition of ARDS by the American and European Consensus Conference (AECC) is based on four criteria focused on physiological abnormalities of the lung (5). This means that the broad variety of etiologies leading to lung dysfunction and failure is not taken into account. It is important to recall here that the definition of ARDS is independent of PEEP, especially in the context that ventilation studies (6,7) were the only positive ARDS trials reported so far. The above described concept of treating ARDS with surfactant is derived from three routes of extrapolation and/or simplification: established ARDS according to AECC definition is treated with single or repetitive high doses of surfactant Correspondence to: Dr Wolfgang Strohmaier, Margaretenstrasse 71/18, 1050 Vienna, Austria (email: Wolfgang.Strohmaier@ gmx.at). Pediatric Anesthesia 2006 16: 813–815 doi:10.1111/j.1460-9592.2006.02015.x

Best Clinical Practice and Evidence-Based Assessment in Pediatric Ventilation Support.

Some of these concerns should be addressed with great care, as many clinical interventions that have not undergone randomized controlled trial (RCT) experimental conditions may actually be believed to have been so tested, whereas some RCTtested interventions may be thought of as untested. Few ICU interventions have RCT evidence to document a positive effect on patient outcomes (2). Furthermore, clinical trial designs raise questions of generalization about their findings outside a limited sample setting. But what if there is no RCT evidence on which to inform a clinical decision? Are there reliable alternatives for the clinician in the absence of such evidence? Are we even able to acknowledge the paucity of evidencebased information in the critical care setting in pediatrics? Ventilatory support is precisely one of these significant areas of pediatric critical care medicine that still awaits an expert consensus. This dilemma, or uncertainty, reflects the nature of our practice and emphasizes the lack of consensus recommendations in major areas of treatment in the PICU. That such issues arise is what makes medicine an art as well as a science (3–7). Carrying out large-scale RCTs may be unfeasible or scarcely possible. The reasons behind this may be linked to enrolment and/or experimental conditions in carrying out the trial study or clinical research proving to be objectively impractical. This makes safe and effective treatments for children difficult to validate according to evidence-based medicine criteria. Can we rely on cohort studies, case-controlled studies, prospective case series, editorials and expert opinion (in the form of consensus conference reports or position statements published by practitioners or experts of acknowledged authority and skill) to assume such relevance for the guidance of methodology? This remains an unresolved question to this day. Possible guidance from the matter in hand may also derive from the founding principle underlying some methodologies of a medicolegal character for the interpretation of damages according to which, before the process of litigation begins, a relevant reference (from a recognized expert) is sought. Hence, in addressing the specifics of the case, one may take advantage of the guidance that others have previously acknowledged (thus using a heuristic technique in the absence of other possible information regarding treatment). This standpoint represents the most common-sense, reasonable approach because, as an alternative when no safe and validated treatment exists, no other way can be found. At issue is that some ventilation methods such as, for example, high frequency oscillatory ventilation (HFOV) or proportional assist ventilation (PAV) and some treatment approaches have imposed themselves and continue to be propounded on the strength of “trends” and/or “routines and preferences” *See also p. e487.

Treatment of septic shock and use of drotrecogin alfa (activated) in children.

Severe sepsis is a complex syndrome and often life-threatening condition caused by the body’s systemic response to an infection, and is accompanied by single or multiple organ dysfunction or failure, leading to death [1]. Sepsis often develops in children with pneumonia, trauma, surgery, burns or cancer, and is frequently underdiagnosed at an early stage when it is still potentially reversible. Sepsis and infection may be present at the same time and, indeed, infection is a prerequisite for sepsis, but the two are not synonymous – infection is the invasion of a tissue or organ by a pathogenic micro organism, while sepsis is the complex, systemic inflammatory response to infection [2]. In children, as in adults, the response to infection leads to the secretion of proand anti-inflammatory cytokines, the activation and mobilization of leukocytes, the activation of coagulation and inhibition of fibrino lysis, and increased apoptosis [3]. As a result of coagulation activation, the thrombin generated promotes fibrin deposition in the microvasculature and exacerbates ongoing inflammation via both direct and indirect mechanisms. These innate inflammatory processes can be detrimental, resulting in cardiac dysfunction, vasodilatation, capillary injury, and microand macro-vascular thromboses. Despite antibiotics and intensive care, these processes frequently lead to organ dysfunction, gangrenous extremities, long-term neurologic morbidity or death [4,5]. Activated protein C is a critical, endogenous regulator of coagulation and inflammation. After activation of plasma protein C by the thrombin–thrombomodulin complex, activated protein C exerts antithrombotic and profibrinolytic effects [6]. The anti-inflammatory effects of activated protein C are, on the one hand, indirect because of the inhibition of thrombin formation and, on the other, direct via the blockage of cytokine formation, and inhibition of selectin activity and nuclear factor-b translocation [7].

Searching for Biomarkers With Predictive Value in Pediatric Acute Lung Injury: Can SpO2/FIO2 Be Used Instead of PaO2/FIO2 as an Index to Predict Outcome?*

The management of acute respiratory pathology in children is principally directed toward early diagnostic recognition, appropriateness of intervention, and reducing side effects. Particular attention has been paid to identifying stronger indices for predicting outcomes. To achieve these goals, on the one hand, a therapeutic approach has aimed at minimizing the invasiveness of the treatment modalities applied and their attendant risks (such as ventilator—associated pneumonia or bronchopulmonary dysplasia), either by applying noninvasive methods (e.g., nasal continuous positive airway pressure, noninvasive ventilation, or high-flow oxygen) earlier in settings where they are indicated or by adopting early extubation strategies. A major role has been played, on the other hand, by the investigation of biomarkers, both clinical and humoral, that allow a correct diagnosis of the pathology to be made and confirm the appropriateness of the treatment that is applied (1). Biomarkers can be broadly defined here as almost any measurement reflecting an interaction between a biological system and an environmental agent, which may be chemical, physical, or biological. This framework for conceptualizing biomarkers should also be applied to acute lung injury (ALI) research and serves as a reminder that clinical signs can also be included among biomarkers (2, 3). The use of ultrasonography as a clinical biomarker in the diagnosis of acute lung pathology and in treatment assessment is undergoing a major expansion. Ultrasonography allows investigation under any set of clinical circumstances with no need for patient immobilization and affords a dynamic assessment of the clinical setting under analysis. The examination can be repeated as many times as considered necessary without exposing patients and their environment to the hazards of ionizing radiation. The combined application of ultrasonography and specific biomarkers may represent an appropriate approach to reduce morbidity and improve survival. The early recognition of disease and application of noninvasive treatments, together with the monitoring of their efficacy, are fundamental to improve patient outcomes (4). Different biomarkers are under investigation in pediatric respiratory care, but none are currently available that are both specific and safe in acute lung pathology. Some biomarkers, such as interleukin-8, soluble receptor of advanced glycation end-products, and angiotensin II, are in use in both children and adults and are able to assess inflammation and alveolar epithelium damage (type-I pneumocytes) but can be present in many other pathologies. Biomarkers of surfactant injury offer a more encouraging outlook, as they are able to evaluate type-II pneumocytes damage and thus the actual level of alveolar involvement in lung disease processes. Surfactant proteins A and B (SP-A, SP-B) have been found in the bronchoalveolar lavage fluid of patients at risk of acute respiratory distress syndrome (ARDS) prior to the onset of clinical symptoms. Reduced pulmonary edema fluid SP-D and elevated plasma SP-A at ARDS onset have been associated with a poor prognosis (5). The ARDSNet ARMA trial, comparing low with standard tidal volume ventilation, found that baseline levels of SP-D were significantly higher in patients who died, and that a rise in plasma SP-D was attenuated by low tidal volume ventilation, thereby suggesting that the clinical benefits of lung-protective *See also p. e131.

Pediatric sepsis: actions to decrease sepsis in children.

The European Society of Pediatric and Neonatal Intensive Care is the physicians’ and nurses’ annual meeting that was held in Verona, Italy from 14 to 17 June 2009, and approximately 1000 participants from around the world (84 countries) attended. The Congress gave an opportunity to experts to discuss ongoing research and exchange opinions on the future development of studies to identify optimal supportive, preventive and therapeutic strategies for sepsis. A wide range of topics were discussed and several lectures, oral presentations and posters were dedicated to sepsis and its treatment. High scientific-level topics were presented, and stimulated much interest and discussion.