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Delivery Room Management of RDS | OMICS International
Journal of Pulmonary & Respiratory Medicine
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Review Article Open Access
Delivery Room Management of RDS
Saima Aftab1* and Jeffrey S Gerdes2
1Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, USA
2Department of Pediatrics Chief Medical Officer, CHOP Care Network Children's Hospital of Philadelphia Perelman School of Medicine, University of Pennsylvania, USA
Saima Aftab, MD
Assistant Professor of Pediatrics, Children's Hospital of Philadelphia
Perelman School of Medicine, University of Pennsylvania, USA
Received date: March 16, 2013; Accepted date: June 13, 2013; Published date: June 17, 2013
Citation: Aftab S, Gerdes JS (2013) Delivery Room Management of RDS. J Pulmon Resp Med S13:003. doi:10.4172/2161-105X.S13-003
Copyright: © 2013 Aftab S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Functional Residual Capacity (FRC); Continuous Positive Airway Pressure (CPAP); Respiratory Distress Syndrome (RDS); Broncho-Pulmonary Dysplasia (BPD); Extremely Low Birth Weight (ELBW) (an infant with birth weight less than 1000 grams); Very Low Birth Weight (VLBW) (an infant with birth weight less than 1500 grams); T Piece Resuscitator (TPR); Self Inflating Bag (SIB); Positive Inspiratory Pressure (PIP); Laryngeal Mask Airway (LMA); Fraction of Inspired Oxygen (FiO2), Minimally Invasive Surfactant Therapy (MIST); Intubation Surfactant Administration followed by Extubation (INSURE) to CPAP
Respiratory Distress Syndrome or RDS is a clinical syndrome characterized by respiratory failure in a preterm neonate. An increasing understanding of lung immaturity came from the discovery of surfactant deficiency in infants who died of RDS, then known as hyaline membrane disease. The immature lung in RDS is deficient in surfactant and is prone to atelectasis, which in turn leads to lung inflammation and poor gas exchange. Before the introduction of mechanical ventilation and CPAP (Continuous Positive Airway Pressure) in the 1960's and 1970's, the only therapy for respiratory failure in the preterm newborn was oxygen and fluids [1].
Surfactant therapy for the treatment of RDS became available in the 1990s. Evidence from a series of surfactant studies indicated a decrease in mortality and morbidities, and led to its widespread acceptance of as standard of care for the prevention and treatment of RDS in preterm infants [2,3].
As the importance of establishing adequate lung volume or Functional Residual Capacity (FRC) early after birth was recognized, more interest in non-invasive methods of achieving this goal through early application of CPAP was investigated. CPAP was of particular interest as it was recognized that the process of intubation could lead to cardiovascular instability, and surfactant administration may itself lead to changes in cerebral blood flow. Those factors, coupled with data from animal studies linking volu-trauma and lung inflammation to future BPD (Broncho-Pulmonary Dysplasia), raised the importance of investigating non-invasive means of support.
Over the past 2 decades, widespread use of antenatal corticosteroids, regionalized care of the ELBW infant, progress in surfactant therapy and ventilatory support strategies, and improved team training in the delivery room have significantly improved survival, short-term complications, and long-term respiratory and neuro-developmental outcomes of the preterm neonate. In this article we will review the evidence for delivery room management of RDS, address controversies surrounding different therapies and explore ways to optimize lung recruitment, oxygen delivery and surfactant administration.
Pathophysiology of RDS
The anatomy and physiology of the preterm lung change dramatically between the periods of viability (23 weeks gestation) to 36 weeks gestation, when the risk of RDS reaches less than 5%. These changes include structural maturation, an increase in surfactant synthesis, and improved ability to clear fetal lung fluid and enhanced epithelial barrier function. These changes influence how surfactant treatment will interact with the lung and affect lung mechanics in the immediate newborn period, as well as how the improvements will change over time.
The fetal lung is filled with fluid secreted by the developing pulmonary epithelium. At birth effective transitioning from placental to pulmonary gas exchange requires removal of fluid from the lung. This process is initiated before birth, is augmented by labor and is completed several hours after independent breathing by the newborn. Both the birth-associated epinephrine surge and an increase in alveolar oxygen tension accelerate lung fluid resorption [4]. A combination of strong breathing effort and lung fluid resorption leads to establishment of lung volume or FRC. This allows spreading of endogenous surfactant further stabilizing lung inflation and facilitating gas exchange. At birth the pulmonary vascular resistance is high; after birth the pulmonary vascular resistance begins to drop, allowing for improved pulmonary blood flow, which in turn also improves oxygenation.
Respiratory Management for RDS in the Delivery Room: The Surfactant Question
Early vs. Late surfactant administration for the treatment of RDS
Initial randomized clinical trials of surfactant therapy in preterm neonates showed improvement in survival without chronic lung disease as well as reduction in the incidence of pneumothorax and air leak syndromes. While these early trials led to FDA approval and widespread adoption of surfactant therapy, ongoing research continued to fine-tune the details of surfactant treatment. One of the major areas of investigation has been the timing of surfactant dosing. Multiple randomized and quasi-randomized trials and the subsequent metaanalyses compared the outcomes for early (within the first two hours of life) compared to later treatment). The Cochrane Data base recently published a meta-analysis looking six large studies, which examined this question [5]. The meta-analyses demonstrated significant reductions in the risk of neonatal mortality (typical risk ratio (RR) 0.84; 95% Confidence Interval (CI) 0.74 to 0.95; typical Risk Difference (RD) -0.04; 95% CI -0.06 to -0.01; 6 studies; 3577 infants), chronic lung disease (typical RR 0.69; 95% CI 0.55 to 0.86; typical RD -0.04; 95% CI -0.06 to -0.01; 3 studies; 3041 infants), and chronic lung disease or death at 36 weeks (typical RR 0.83; 95% CI 0.75 to 0.91; typical RD -0.06; 95% CI -0.09 to -0.03; 3 studies; 3050 infants) associated with early treatment of intubated infants with RDS. Intubated infants randomized to early selective surfactant administration also demonstrated a decreased risk of acute lung injury including a decreased risk of pneumothorax (typical RR 0.69; 95% CI 0.59 to 0.82; typical RD -0.05; 95% CI -0.08 to -0.03; 5 studies; 3545 infants), pulmonary interstitial emphysema (typical RR 0.60; 95% CI 0.41 to 0.89; typical RD -0.06; 95% CI -0.10 to -0.02; 3 studies; 780 infants), and overall air leak syndromes (typical RR 0.61; 95% CI 0.48 to 0.78; typical RD -0.18; 95% CI -0.26 to -0.09; 2 studies; 463 infants). A trend toward risk reduction for broncho Pulmonary Dysplasia (BPD) or death at 28 days was also evident (typical RR 0.94; 95% CI 0.88 to 1.00; typical RD -0.04; 95% CI -0.07 to -0.00; 3 studies; 3039 infants). No differences in other complications of RDS or prematurity were noted [5].
Summary: Surfactant should be administered promptly when a preterm infant requires intubation and ventilator support for established RDS.
CPAP vs. Intubation/surfactant/ventilation as initial respiratory management in the delivery room
The early trials of surfactant treatment focused on babies who were intubated for respiratory support. As experience was gained with alternative non-invasive support strategies for RDS, the question was raised as to how to balance the proven benefits of surfactant therapy with the potential for reduced risk and improved outcomes with noninvasive support such as CPAP.
In the very beginning Aly et al. [6] performed a retrospective cohort study to evaluate the effect of an early nasal policy on outcomes of extremely low birth weight infants. They enrolled a total of 234 infants of which 83 infants, born before the CPAP policy, were intubated in the delivery room. 151, born after the policy, were placed on CPAP in the delivery room. A multivariate analysis for important factors showed that infants who were never intubated received fewer days of oxygen than infants who were briefly intubated in the delivery room and also had a lower death rate. Importantly in this study they found that a high percentage of infants who were tried on CPAP did not fail and there was no untoward effect of failing CPAP and requiring intubation [6].
Several randomized clinical trials have compared delivery room CPAP to mandatory intubation and ventilation. In the COIN trial (CPAP or Intubation at birth Trial), Morley et al. studied 610 infants born at 25-28 weeks gestational age. They found a non-statistically significant trend toward decreased rate of the primary outcome, death or BPD at 36 weeks corrected age, in the CPAP group. (33.9% vs. 38.9%, OR 0.80, 95% Cl 0.58, 1.12) [7]. There was, however, a significant increase in the rate of pneumothorax in the CPAP group [7].
In the SUPPORT trial (Surfactant Positive Pressure and Oxygen Randomized Trial) the NICHD Neonatal Research Network randomized 1316 infants born at 24-27 6/7 weeks to early CPAP in the delivery room or intubation and surfactant [8]. Again, the authors found a non-statistically significant trend toward decreased rate of the primary outcome, death or BPD at 36 weeks, in the CPAP group (47.8% vs. 51.0%, RR 0.95, 95% CI 0.85, 1.05). In this study, there were more infants in the CPAP arm alive and extubated at 7 days of life (55.3% vs. 48.8%, p=0.01) and fewer infants in the CPAP arm who received steroids for BPD (7.2% vs. 13.2%, p<0.001), without an increase in air leaks [8].
Further, a Vermont Oxford Network study randomized 648 infants born at 26-29 6/7 weeks gestation to intubation/prophylactic surfactant/mandatory ventilation, intubation/prophylactic surfactant/ extubation to CPAP, or CPAP alone [9]. They also found a nonstatistically significant trend towards less death or BPD at 36 weeks in the CPAP group when compared to the group who received mandatory ventilation in the delivery room (30.5% vs. 36.5%, OR 0.83, 95% CI 0.64, 1.09) [9]. When the 2358 infants from these studies are combined, there is a highly significant reduction in the odds of death or BPD at 36 weeks corrected age associated with the use of CPAP in the delivery room, odds ratio 0.80 (95% CI 0.68, 0.94).
The recently published trial of early CPAP by the South American Neocosur Network randomized infants to early CPAP or oxygen hood [10]. Surfactant was administered to both groups if the fraction of inspired oxygen concentration exceeded 35%. There was a reduction of the need for mechanical ventilation and the BPD/death rate tended to be lower in the early CPAP group. In addition to early CPAP, some recent trials have also tested an early surfactant strategy in addition to early CPAP. The trial by Verder et al. [11] initially managed infants on nasal CPAP immediately after birth and randomized infants to early surfactant administration or no early surfactant. This trial was stopped when an interim analysis showed that nasal CPAP with early surfactant administration significantly reduced the need for mechanical ventilation during the first week of life.
The CURPAP [12] and Colombian Network 4trials compared early CPAP with or without surfactant and reported that there was no difference in BPD rates between treatment strategies. However, there was a 9.1% lower BPD/death rate in the surfactant-treated infants in the Colombian trial [13] (53.9% in the CPAP surfactant group versus 62.8% in the CPAP only group) but it did not reach statistical significance.
Summary: CPAP started soon after birth is a strategy that appears to reduce BPD/death and is an alternative to the prophylactic or early surfactant approach. Infants treated with early CPAP instead of early surfactant are not at increased risk of adverse outcomes from delaying or eliminating surfactant administration. Thus, early CPAP is recommended based on the most recent evidence, with the caveat that babies who develop respiratory failure and require intubation and ventilator care receive surfactant treatment promptly after intubation.
Is there harm to intubating infants in the delivery room?
In an analysis of the Caffeine for Apnea of Prematurity trial, DeMauro and colleagues demonstrated a significant trend toward increased rates Of Broncho Pulmonary Dysplasia (BPD) in infants who were intubated in the delivery room, even when adjusting for multiple important prognostic factors [14].
The INSURE method vs. CPAP in initial respiratory management
An alternate approach to delivery room CPAP is the INSURE method, in which infants are intubated, receive surfactant, and then are immediately extubated to CPAP. The benefit of this approach would be early administration of surfactant to any infant at risk for developing Respiratory Distress Syndrome (RDS). When compared to late, selective surfactant, early prophylactic surfactant reduces death or BPD in infants born <30 weeks and with established RDS [15]. Therefore, routine early prophylactic surfactant is an attractive approach. Unfortunately, this strategy has never been directly compared to CPAP alone in a randomized trial. Furthermore, the studies that established the superiority of early surfactant did not use CPAP support in their control arms and were performed in the era before routine use of antenatal steroids. The Vermont-Oxford Network study discussed above had INSURE and CPAP arms with equivalent results; however, these arms have not been directly compared to each other in the study's publications to date. Thus, the data in support of routine administration of delivery room CPAP is far stronger than the data in support of routine INSURE. It is important to emphasize that many of the subjects in the above trials who were randomized to delivery room CPAP did, eventually, require intubation and surfactant treatment.
The possible benefits of CPAP and INSURE was seen a recently published study comparing respiratory outcomes in two time epochs before and after introduction of early nasal CPAP and INSURE in the delivery room management of RDS. They observed a decrease in need for intubation, mechanical ventilation, oxygen therapy and mortality since the introduction of CPAP and INSURE. They also found a trend for lower BPD even though it did not reach statistical significance [16].
Summary: Hence we conclude that while delivery room CPAP is not expected to prevent all intubation events, there is no evidence of harm associated with starting CPAP in the delivery room. For those babies who require intubation for RDS INSURE may be a reasonable approach.
Use of surfactant when intubated for respiratory failure
For completeness, based on a 1999 Cochrane Review on early versus delayed selective surfactant treatment for RDS, which demonstrated reduced risk of death and/or CLD with early versus late surfactant in intubated infants, all ELBW infants who are intubated in the first 48 hours of life should receive at least one dose of surfactant [15].
Animal derived versus synthetic surfactants
A wide variety of surfactant preparations have been developed and tested. These include synthetic surfactants and surfactants derived from animal sources. Although clinical trials have demonstrated that both synthetic surfactants and natural surfactant preparations are effective, comparison in animal models has suggested that there may be greater efficacy of natural surfactant products, perhaps due to the protein content of natural surfactant [17]. Several randomized control trials have tried to compared safety and efficacy of natural versus synthetic surfactant. A meta-analysis of these randomized control trials published by Cochrane. The meta-analysis shows that the use of natural surfactant rather than synthetic surfactant results in a significant reduction in the risk of pneumothorax and the risk of mortality [18]. Natural surfactant extract is associated with a marginal increase in the risk of intraventricular hemorrhage (typical relative risk 1.09, 95% CI 1.00, 1.19; typical risk difference 0.03, 95% CI 0.00, 0.06), but no increase in grade 3 to 4 intraventricular hemorrhage (typical relative risk 1.08, 95% CI 0.92, 1.28; typical risk difference 0.01, 95% CI -0.01, 0.03). The meta-analyses support a marginal decrease in the risk of bronchopulmonary dysplasia or mortality associated with the use of natural surfactant preparations. No other relevant differences in outcome are noted. Both natural surfactant extracts and synthetic surfactant extracts are effective in the treatment and prevention of respiratory distress syndrome. Comparative trials demonstrate greater early improvement in the requirement for ventilator support, fewer pneumothoraces, and fewer deaths associated with natural surfactant extract treatment [18].
Summary: Natural surfactant extracts would seem to be the more desirable choice when compared to currently available synthetic surfactants.
MIST and other methods of surfactant administration
The beneficial effects of INSURE is likely due to surfactant administration, which led to interest in minimally invasive methods of administrating surfactant so the benefit could be delivered without the potential deleterious effects of intubation and mechanical ventilation. MIST would involve administering surfactant through a fine catheter directly into the trachea on a spontaneously breathing infant stabilized on nasal CPAP. This was investigated in the Avoidance of Mechanical Ventilation Trial that randomized 220 babies between 26-28 weeks gestational age BW<1500 g to either MIST or continuation of CPAP. This study not only demonstrated that this was feasible as the MIST was completed in the first attempt in 95% cases but it also showed that the babies undergoing MIST treatment had less need for mechanical ventilation and less need for oxygen at 28 days of life. MIST did not affect overall survival and no studies comparing MIST to INSURE are available [19]. Other techniques such as administering nebulized surfactant or nasopharyngeal surfactant or LMA (Laryngeal Mask Airway) surfactant administration has not been widely studied to determine if it is of any utility.
Methods of administering surfactant (ventilator vs hand bagging) Fractionated versus bolus dosing
There is some variation in the methods of surfactant administration such as bolus versus fractionating the dose, variations in infant positioning during administration interruption of mechanical ventilation and hand bagging versus administering through a side port adapter while remaining on mechanical ventilation. A randomized trial comparing surfactant administration as two or four fractionated aliquots did not find any difference in either fractional inspired oxygen, mean airway pressure, and arterial-alveolar ratio of partial pressure of oxygen at 72 hours of life, or in the incidences of air leaks, pulmonary interstitial emphysema, or death through 72 hours of life. There were no significant differences in the lowest heart rates recorded during administration of doses. The same study compared surfactant administration with hand bagging versus on mechanical ventilation and found that while giving the first dose there was less incidence of oxygen desaturation with mechanical ventilation than with hand bagging [20].
Another randomized trial compared surfactant administration in 2 aliquots followed by hand bagging versus single aliquot given through a side port adapter of the ETT over a minute while remaining on mechanical ventilation. The number of episodes of hypoxia and bradycardia were similar in both groups. A slight transient increase in PaCO2 was seen in the side hole group, however the efficacy of surfactant based on oxygenation and ventilation improvement was similar. There was also no difference in the incidence of IVH air leaks PDA BPD or survival in either group. This study showed no difference in the efficacy or side effect profile with surfactant administration either by hand bagging or mechanical ventilation [21]. While not formally studied in a detailed manner, maintaining FRC during surfactant administration is likely to benefit the RDS lung, since having adequate FRC is in itself a known benefit for treatment of RDS. The optimum tactic is to maintain patient stability and FRC through use of a ventilator or t-piece resuscitator during surfactant administration.
Summary: Surfactant should be administered while maintaining FRC with a ventilator or T-piece resuscitator, and given in no more than two aliquots for each dose.
Respiratory Management for RDS in the Delivery Room: Questions Surrounding Non Invasive Respiratory Support
NIPPV
There has been substantial interest in the use of noninvasive ventilation for preterm infants, aiming to reduce invasive mechanical ventilation and associated complications [22]. The need for mechanical ventilation, especially early in life, is a major risk factor for the complex disorder of Broncho-Pulmonary Dysplasia (BPD) [23]. Nasal Continuous Positive Airway Pressure (NCPAP) is an initial respiratory support mode for many preterm infants with Respiratory Distress Syndrome (RDS), and this may have contributed to a significant decrease in the incidence of BPD at some centers. However, some infants fail NCPAP, and a newer noninvasive strategy that uses Nasal Intermittent Positive-Pressure Ventilation (NIPPV), with or without synchronization, has gained popularity as a mode of respiratory support for these infants [24]. A recent meta-analysis of several studies showed that among preterm infants with respiratory distress syndrome, NIPPV decreased the need for invasive ventilation within the first 72 hours of life compared with NCPAP. Trials are however still needed to assess whether NIPPV minimizes the occurrence of broncho-pulmonary dysplasia and other co-morbidities [25].
T piece resuscitator or a bag mask device
Effective positive pressure ventilation can be vital to neonatal resuscitation; in addition it is also important for uniform and effective surfactant distribution. A T piece resuscitator TPR or the traditional flow bag valve mask apparatus can deliver this positive pressure [26]. The TPR provides pressure controlled, flow delivered positive pressure ventilation. The Positive End Expiratory Pressure (PEEP) valve can be rotated to modify the PEEP provided, and occlusion of the valve by the operator delivers Peak Inspiratory Pressure (PIP). Its main purported advantages are the delivery of consistent pressures, the ability to adjust inspiratory time, and the control of PIP and PEEP [27]. There is a wide variability in the use of T piece resuscitator in neonatal resuscitations. There are several studies trying to compare the T piece resuscitator to the flow-inflating bag.
Dawson et al. [28] randomized infants less than 29 weeks' gestation to receive positive pressure ventilation with the Neopuff or the Self-Inflating Bag (SIB), and did not find a significant difference in mortality, need for endotracheal intubation or the need for respiratory support at 28 days. They also did not find a significant difference in oxygen saturation at 5 min (Neopuff 49%, SIB 59%) or heart rate at 5 min (Neopuff 135, SIB 138).
There are several mannequin studies comparing the T piece resuscitator to the self inflating or flow inflating bags on variables of ability to deliver target pressures, I time and Tidal volume variability and role of teaching for effectiveness of ventilation. TPR can provide PIPs that are closest to the target PIP with least variation when compared to users of the SIB and FIB. Similarly TPR users should be able to provide a PEEP that is closer the predetermined PEEP value [29]. Volu-trauma may potentially be less likely with the TPR as tidal volumes are smaller [30] and fewer variables in comparison to the SIB operators. TPR can provide a more consistent inspiratory time than SIB [29,31] and this does not depend on experience level [31].
TPR users should also be aware of certain limitations of the device. Resuscitation is a dynamic process where the resuscitator needs to adapt to the response or non-response of the newborn. TPR users are not as good at detecting changes in compliance as users of the Self or Flow Inflating bags. TPR users also need more time to change the inflating pressures during resuscitation, compared to users of the SIB or FIB. Mask leak is greater with the TPR than with other devices.
TPRs are also the most technically difficult of the 3 devices to prepare for use. Operators who do not frequently use the device, and are not receiving regular training in its setup, forget how to prepare the device for use. Instructors should be aware that increases in gas flow before, or during resuscitation could result in significant increases in pressures unless the operator adjusts the dials accordingly.
Until evidence of clinical benefit is available, we recommend that healthcare providers are appropriately and regularly trained in the use of whatever device being used in their clinical practice, and are aware of the particular limitations of that device.
Bubble CPAP versus variable flow CPAP
NCPAP can be administered via a constant flow system such as the traditional bubble CPAP device or a variable flow CPAP system. The safety and efficacy of Nasal Continuous Positive Airway Pressure (NCPAP) using devices with variable flow or bubble Continuous Positive Airway Pressure (CPAP) has been studied in randomized control trials has shown, no differences in CPAP failure, air leak syndromes and total CPAP time [32]. In babies previously intubated for RDS, extubation to bubble CPAP compared to a variable flow system was associated with a considerably shorter CPAP duration. The median duration of CPAP support was 50% shorter in the infants on bubble CPAP. Moreover, in the subset of infants who were ventilated for less than 14 days, the infants on bubble CPAP had a significantly lower extubation failure rate. There was no difference in the incidence of chronic lung disease or other complications between the 2 study groups [33]. Both constant and variable flow systems are safe and effective for CPAP delivery, bubble CPAP may offer an advantage for infants intubated <14 days in terms of less extubation failure, but this does not translate to less BPD. Bubble CPAP is inexpensive, easy to set up, and is of particular value in developing countries with scare resources. However as the level of CPAP is determined by the depth of insertion of the tubing in a water column, it requires close attention and substantial nursing care to avoid inadvertent excessive CPAP leading to barotrauma [34].
Respiratory Management for RDS in the Delivery Room: The O2 Question
Natural history of oxygen saturations after birth
In utero, fetal oxygen saturation is approximately 60%. Full-term babies may take more than 10 minutes for oxygen saturations to be above 90%, though the majority reach >90% by 5-8 minutes [35]. Oxygen saturations measured post-ductally increase at a slower rate than those measured pre-ductally [36]. There is a slower rise in oxygen saturations after cesarean section delivery, compared to vaginal delivery [37]. Lastly, preterm neonates have a slower rise in oxygen saturations than term infants, and values overall remain lower. For example, at 5 minutes of life and without intervention, the 50th percentile of saturations in infants <32 weeks is 86% and the 10th percentile is 72% [38] compared to 92% and 75%, respectively, in the term baby. Despite the fact that normal transition is associated with a slow rise in oxygen saturation, it is common delivery room practice to monitor oxygen saturation in very low birth weight infants and to provide supplemental oxygen within the first minutes of life, to increase the oxygen saturation. The safety of this practice has never been demonstrated and several studies suggest harm.
Safety of room air resuscitation in term infants and larger preterm infants
Recent studies have evaluated the safety of room air, rather than supplemental oxygen, for infant resuscitation. When neonates >1000 grams were resuscitated with room air, there was no difference in mortality, hypoxic ischemic encephalopathy, length of resuscitation (time to first cry was shorter), or "treatment failure" [39]. There was no difference in growth, attainment of developmental milestones, hearing, cerebral palsy or mental retardation at 18 or 24 months of age [40]. A meta-analysis of 6 randomized and 4 quasi-randomized trials showed a significant reduction in mortality for infants resuscitated in RA vs. 100% oxygen (randomized: RR 0.32(0.12-0.84), quasi-randomized: RR 0.74(0.57-0.95), all: RR 0.69(0.54-0.88) [41].
Harm associated with resuscitation with 100% oxygen
Furthermore, some studies suggest harm associated with 100% oxygen resuscitation. When asphyxiated term neonates were resuscitated with 100% oxygen or room air, the infants resuscitated with room air had shorter time to first cry and return of regular respiratory pattern, shorter length of resuscitation, and lower markers of oxidative stress at 48 hours and 28 days of life [42]. Furthermore, there are two casecontrol studies demonstrating a higher incidence of childhood cancer in infants exposed to as little as 3 minutes of oxygen in the delivery room when compared to those never exposed to oxygen [43,44].
Studies of high vs. low starting oxygen levels in preterm infants (including ELBWs)
Four studies have evaluated the differences between high and low oxygen resuscitation for preterm infants. Wang and colleagues found infants failed to reach the goal saturations of 70% at 3 minutes and 85 at 5 minutes of life when they were started on room air. When compared to the group resuscitated with 100% oxygen, there were no differences in heart rate at any time in the first 10 minutes of life or in any of the secondary outcomes [45].
In the ROAR study, investigators studied 106 infants less than 32 weeks gestation. The infants were assigned to one of three groups: 1) start at 100% and do not titrate, 2) start at 100% and titrate down based on oxygen saturation, or 3) start at 21% and titrate up based on SpO2. A significantly higher percentage of infants in the groups with the titrating protocols spent time in the target saturation range of 85-92% [46].
Escrig and colleagues conducted a randomized trial of 42 infants with birth weight less than 1000 grams. Resuscitation was started at 30% in one group and 90% in the other. FiO2 was adjusted by 10% every 60 to 90 seconds to keep the heart rate above 100 and achieve a saturation goal of 70% at 5 minutes and 85% at 10 minutes. The low oxygen group ultimately had a stepwise increase in inspired oxygen to 45%, while the high oxygen group had a reduction in inspired oxygen to 45%. Both groups had saturations of about 85% at 5 to 7 minutes of life and they found no difference in mortality [47].
Finally, Vento et al. [48] continued the Escrig study for an additional year, to evaluate rates of Broncho Pulmonary Dysplasia (BPD), defined as oxygen requirement at 36 weeks post conceptual age, based on initial oxygen exposure. They found that the low oxygen group had lower rates of BPD, fewer days of oxygen supplementation and mechanical ventilation, and lower markers of oxidative stress [48].
Based on this evidence, we arrived at the following recommendations for the management of oxygen in the delivery room.
1. Place pulse oximetry probe on infant's right hand, the preductal location.
2. Start at 30% oxygen and titrate by 10% every minute to achieve target saturation.
3. Goal oxygen saturation is:
a. 70% by 5 minutes of life
b. 85-92% by 10 minutes of life
If the infant has prolonged bradycardia (HR<100), may increase immediately to 100% oxygen (Figure 1).
*Consider INSURE intubation with surfactant administration following by early extubation to CPAP
Figure 1: Recommendations for DR Management of RDS.
Non-invasive respiratory support is the first line therapy for all ELBW infants:
Establish a team leader, usually a neonatology fellow or attending.
Airway - experienced personnel, usually a senior nurse practitioner, fellow or attending
Routine gentle bulb suction and stimulation
Immediately initiate CPAP 5cm and titrate (max 8 cm) to reduce work of breathing and O2 requirement
Use CPAP interface that allows the infant to be placed on the ventilator in the resuscitation room if possible during umbilical line insertion.
Intubation criteria:
0. HR<100 or hemodynamic instability
i. PCO2>65
ii. FiO2>60% to maintain saturations per oxygen guidelines
iii. Apnea or severe distress
iv. Established RDS with rising oxygen requirement in the first 24 hours of life
When in doubt, the INSURE (intubate, give surfactant, extubate to CPAP) approach seems to be an acceptable alternative until more data from randomized trials are available.
For infants on CPAP, start caffeine immediately upon admission to neonatal intensive care unit
All ELBW infants intubated in the first 48 hours of life should receive at least one dose of surfactant promptly after intubation.
Continue to foster a culture that supports use of non-invasive respiratory support in the delivery room and in the unit
Pay attention to other aspects of care of the newborn such as thermoregulation and establishing access.
Improvement in perinatal care has resulted in improved respiratory outcomes in newborns with RDS. Combining years of neonatology experience with current day evidence will help ensure that we optimize management of RDS. It is essential to have excellent teamwork and communication in the delivery room. It is extremely important to establish early lung recruitment and CPAP appears to be a reasonable initial approach. Once it is evident that a baby is failing CPAP the baby should be intubated for prompt surfactant administration. Although good studies are lacking INSURE may be considered provided the baby has good respiratory effort and has a reasonable expectation to be able to tolerate extubation to CPAP. Novel methods of surfactant administration via LMA and MIST seem to have promise but more studies will need to be done to determine their safety and efficacy. Close attention should be paid to the oxygen saturations in the delivery room. FiO2 should be carefully titrated to keep saturations within target range.
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Verder H, Albertsen P, Ebbesen F, Greisen G, Robertson B, et al. (1999) Nasal continuous positive airway pressure and early surfactant therapy for respiratory distress syndrome in newborns of less than 30 weeks' gestation. Pediatrics 103: E24.
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Rojas MA, Lozano JM, Rojas MX, Laughon M, Bose CL, et al. (2009) Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics 123: 137-142.
DeMauro SB, Roberts RS, Davis P, Alvaro R, Bairam A, et al. (2011) Impact of delivery room resuscitation on outcomes up to 18 months in very low birth weight infants. J Pediatr 159: 546-550.
Soll RF, Morley CJ (2001) Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev: CD000510.
Flor-de-Lima F, Rocha G, Guimarães H (2012) Impact of changes in perinatal care on neonatal respiratory outcome and survival of preterm newborns: an overview of 15 years. Crit Care Res Pract 2012: 643246.
Tooley WH, Clements JA, Muramatsu K, Brown CL, Schlueter MA (1987) Lung function in prematurely delivered rabbits treated with a synthetic surfactant. Am Rev Respir Dis 136: 651-656.
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Göpel W, Kribs A, Ziegler A, Laux R, Hoehn T, et al. (2011) Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet 378: 1627-1634.
Zola EM, Gunkel JH, Chan RK, Lim MO, Knox I, et al. (1993) Comparison of three dosing procedures for administration of bovine surfactant to neonates with respiratory distress syndrome. J Pediatr 122: 453-459.
Valls-i-Soler A, López-Heredia J, Fernández-Ruanova MB, Gastiasoro E (1997) A simplified surfactant dosing procedure in respiratory distress syndrome: the "side-hole" randomized study. Spanish Surfactant Collaborative Group. Acta Paediatr 86: 747-751.
Ramanathan R (2010) Nasal respiratory support through the nares: its time has come. J Perinatol 30 Suppl: S67-72.
Jobe AH (2011) The new bronchopulmonary dysplasia. Curr Opin Pediatr 23: 167-172.
Bhandari V (2010) Nasal intermittent positive pressure ventilation in the newborn: review of literature and evidence-based guidelines. J Perinatol 30: 505-512.
Meneses J, Bhandari V, Alves JG (2012) Nasal intermittent positive-pressure ventilation vs nasal continuous positive airway pressure for preterm infants with respiratory distress syndrome: a systematic review and meta-analysis. Arch Pediatr Adolesc Med 166: 372-376.
Hawkes CP, Ryan CA, Dempsey EM (2012) Comparison of the T-piece resuscitator with other neonatal manual ventilation devices: a qualitative review. Resuscitation 83: 797-802.
Kattwinkel J, Denson S, Zaichkin J (2006) Textbook of neonatal resuscitation (5thedn), American Academy of Pediatrics.
Dawson JA, Schmölzer GM, Kamlin CO, Te Pas AB, O'Donnell CP, et al. (2011) Oxygenation with T-piece versus self-inflating bag for ventilation of extremely preterm infants at birth: a randomized controlled trial. J Pediatr 158: 912-918.
Hussey SG, Ryan CA, Murphy BP (2004) Comparison of three manual ventilation devices using an intubated mannequin. Arch Dis Child Fetal Neonatal Ed 89: F490-F493.
Roehr CC, Kelm M, Fischer HS, Bührer C, Schmalisch G, et al. (2010) Manual ventilation devices in neonatal resuscitation: tidal volume and positive pressure-provision. Resuscitation 81: 202-205.
Roehr CC, Kelm M, Proquitté H, Schmalisch G (2010) Equipment and operator training denote manual ventilation performance in neonatal resuscitation. Am J Perinatol 27: 753-758.
Yagui AC, Vale LA, Haddad LB, Prado C, Rossi FS, et al. (2011) Bubble CPAP versus CPAP with variable flow in newborns with respiratory distress: a randomized controlled trial. J Pediatr (Rio J) 87: 499-504.
Gupta S, Sinha SK, Tin W, Donn SM (2009) A randomized controlled trial of post-extubation bubble continuous positive airway pressure versus Infant Flow Driver continuous positive airway pressure in preterm infants with respiratory distress syndrome. J Pediatr 154: 645-650.
Gunlemez A, Isken T (2008) Bubble CPAP must be used with care to avoid harm. Arch Dis Child Fetal Neonatal Ed 93: F170-F171.
Kamlin CO, O'Donnell CP, Davis PG, Morley CJ (2006) Oxygen saturation in healthy infants immediately after birth. J Pediatr 148: 585-589.
Toth B, Becker A, Seelbach-Göbel B (2002) Oxygen saturation in healthy newborn infants immediately after birth measured by pulse oximetry. Arch Gynecol Obstet 266: 105-107.
Rabi Y, Yee W, Chen SY, Singhal N (2006) Oxygen saturation trends immediately after birth. J Pediatr 148: 590-594.
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Saugstad OD, Ramji S, Soll RF, Vento M (2008) Resuscitation of newborn infants with 21% or 100% oxygen: an updated systematic review and meta-analysis. Neonatology 94: 176-182.
Vento M, Asensi M, Sastre J, García-Sala F, Pallardó FV, et al. (2001) Resuscitation with room air instead of 100% oxygen prevents oxidative stress in moderately asphyxiated term neonates. Pediatrics 107: 642-647.
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Voto valorativo o cardinal se refiere a cualquier sistema electoral que le permite al votante darle a cada candidato una evaluación independiente, típicamente una calificación o rango de calificaciones. Estos también se conocen como sistemas de votación "calificados", "evaluativos", "ranqueados" o "absolutos". Los métodos cardinales (basados en la utilidad cardinal) y los métodos ordinales son dos categorías principales de los sistemas de votación modernos, junto con los sistemas de pluralidad.

Variantes

Existen varios sistemas de votación que permiten calificaciones independientes de cada candidato. Por ejemplo:

 Voto aprobatorio es el método más simple posible, que permite solo dos calificaciones (0, 1): "aprobado" o "no aprobado/rechazado".
 El voto evaluativo o el voto de aprobación combinada utiliza 3 grados (-1, 0, +1): "en contra", "abstenerse" o "a favor".
 En el voto por puntaje o rango, las puntuaciones son numéricas y el candidato con la puntuación media más alta (o total) es quien gana.
 La votación por puntaje utiliza una escala entera discreta, normalmente de 0 a 5 o de 0 a 9.
 La votación por rango utiliza una escala continua de 0 a 1.
 El método de promedios mayores eligen al candidato con la calificación mediana más alta. Las diversas reglas de mediana más alta difieren en sus métodos de desempate. El juicio mayoritario, en el que las calificaciones se asocian a expresiones (como "Excelente", a "Pobre"), es el ejemplo más común, ya que es la primera regla de este tipo que se ha estudiado, pero desde entonces se han propuesto otras reglas, por ejemplo, el juicio típico o el juicio usual.
 Votación STAR (acrónimo en inglés para «Puntaje y Luego Segunda Vuelta Automática»), en la que los puntajes son de 0 a 5, y gana el más preferido de los dos candidatos con mayor puntaje.
 Voto de aprobación mayoritaria, una variante puntuada de la votación de Bucklin, que generalmente usa calificaciones con letras (como "A" a "F").
 Votación 3-2-1, en la que los votantes califican a cada candidato como "Bueno", "OK" o "Malo", y hay tres pasos de eliminación automática para contarlos: el primer paso selecciona los tres candidatos con la mayoría de las calificaciones "Bueno", en segundo lugar los dos con menos "Malos", y de estos gana el preferido por la mayoría.
 Voto acumulativo, donde los puntajes en una boleta deben sumar un monto total fijo.

Además, varios sistemas cardinales tienen variantes para elecciones de múltiples ganadores, generalmente destinadas a producir una representación proporcional, como:

 Voto aprobatorio proporcional
 Voto aprobatorio proporcional secuencial
 Voto aprobatorio por satisfacción
 Voto por rango reponderado

Relación con las clasificaciones
Las papeletas de clasificación se pueden convertir en papeletas de clasificación/preferenciales. Por ejemplo:

Esto requiere que el sistema de votación se adapte a la indiferencia de un votante entre dos candidatos (como en los pares clasificados o el método Schulze).

Lo contrario no es cierto: las clasificaciones no se pueden convertir en clasificaciones, ya que las clasificaciones contienen más información sobre la fuerza de la preferencia, que se destruye cuando se convierte en clasificaciones.

Análisis
Al evitar la clasificación (y su implicación de una reducción monótona de aprobación del candidato más preferido al menos preferido), los métodos cardinales de votación pueden resolver un problema muy difícil:

Un resultado fundamental en la teoría de la elección social (el estudio de los métodos de votación) es el teorema de imposibilidad de Arrow, que establece que ningún método puede cumplir con todo un conjunto simple de criterios deseables. Sin embargo, dado que uno de estos criterios (la universalidad) requiere implícitamente que un método sea ordinal, no cardinal, el teorema de Arrow no se aplica a los métodos cardinales.

Otros, sin embargo, argumentan que las calificaciones son fundamentalmente inválidas, porque las comparaciones interpersonales significativas de utilidad son imposibles. Esta fue la justificación original de Arrow para considerar solo sistemas clasificados, pero más adelante en su vida afirmó que los métodos cardinales son "probablemente los mejores".

La investigación psicológica ha demostrado que las calificaciones cardinales (en una escala numérica o Likert, por ejemplo) son más válidas y transmiten más información que las clasificaciones ordinales para medir la opinión humana.

Referencias

Enlaces externos

Sistemas electorales
Psefología

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. Ephraim was prob a s/o John Goad (#235).
. b ca 1804-05 Tenn; prob d 1870's.
. m(2) Susannah W. Jester, b ca 1808 Ga, prob d 1870's, d/o Jacob Jester and Sidney Susannah Spencer.
. 1830 Campbell Co, Tenn census, p 239, Ephraim Goad, 22001-00001.
. 1840 Hamilton Co, Tenn census, p 171, Ephraim Goad, 022101-110001.
. Susannah M.,13 Ga, Ephraim T.T.,11 Ga, Phoebe E.J.,9 Tenn.
. farm, Phebia E.,19 Tenn.
23541 ? 1. William A. Goad, b ca 1822 Tenn, m Martha J. ____.
. Moved to Marion and Monroe Co's, Tenn and Whitfield Co, Ga.
23542 ? 2. John Lafayette Goad, b ca 1827 Tenn, m Elizabeth Dulcine Wesson (Lizzie).
. Moved to Walker and Chattooga Co's, Ga. Widow was in Jefferson Co, Ala in 1900.
23543 3. Emanuel Goad, b ca 1827 Tenn, m Mary A. Winchell.
. Moved to Lawrence Co, Ark.
23544 4. Robert H. Goad, b 15 Mar 1828 Tenn, m(1) Celia Johnson Benson (Selah,Sely), m(2) Mendosia J. Ward (Minnie).
. Lived in McNairy Co, Tenn, Lawrence and Sharp Cos, Ark, and Parker Co, Tex.
23545 5. Oliver D. Goad, b ca 1831-32 Tenn, m Sarah A. R. ____.
. 6. Nancy Ann Goad, b 4 Feb 1834 Hamilton Co, Tenn, m Albert G. Moore, b ca 1830 Ark.
. 7. Tabitha T.(?J.) Goad, b ca 1836 Tenn.
23546 8. General Harrison Goad, b ca 1836-40 Tenn (or Ga), m Sarah E. (Sallie) ____.
. Moved to Pulaski, Madison, and Lonoke Co's, Ark.
. b ca 1824 NC, and m(3) 1889 to Martha (Lytle) McCowen. Sarah had m(1) John Quinn, b ca 1833 NC.
. 1860 Carroll Co, Ark census, Osage Twp, p 195, #1304/1275, James J. Martindale,23 Ala, --, $100, Minerva C.,17 Tenn.
. Tenn, Mary,8 Ark, Tennessee,5 Ark, William,3 Ark.
. dau) Sarah E.,15 Iowa (stepdau), Cora E.,13 Ohio (stepdau), Grant C.,11 Ind (stepson), laborer.
. John R. Wagnon and Perlina Pauline Prenctice.
. b. Tennessee Martindale (Tennie), b Dec 1862 Ark, m 1884 Ark to Lenard Barnes (Len), b Mar 1845 Ark.
. d. Ephram Thomas Martindale, b 1871 Ark, d 1946 Okla, m Anna M. Smith, b 17 Jan 1873 Mo, d Feb 1980.
. die), b 10 Oct 1892, d 5 eb 1985 Okla. He had previously married.
. Jaggars (later changed to Jaggers).
. Lennan Co, m Hezekiah Kye Chaney.
. 1870 and 1880 census', family not located.
. 1827 or 1843 Ala. James m(2) Elviry ____, b ca 1848 Tenn.
. Ernestine,4 Ark, Susan V.,3 Ark, James E.,1 Ark.
. 1880 Carroll Co census, Piney Twp, p 226D, #11/11, A. Hambay,37 Ala, Elviry,32 Tenn, plus 13 children.
23547 12. Ephraim T. Taylor Goad (Taylor), b May 1850 Tenn, m Jane Terry Hulsey.
. Moved to Cowlitz Co, Wash and Josephine and Multnomah Co's, Ore.
. 13. Phoebe Elizabeth J. Goad, b ca 1851 Tenn.
. 4. Sharon Hill's website. She lists Emanuel Goad, above, as s/o Ephraim C. Goad, s/o James M. Goad (#245).
. heirs does not include Ephraim, except the Ephraim, son of his deceased son Robert.
. 5. Sherry Noble's email: slnoble.noble@gmail.com. She is a descendant of Minerva Catherine Goad above.


After Pearl Harbor, he volunteered for the Army and, via a series of accidents, found himself in the infantry, where he will trace the whole history of American involvement in the European Theater, from North Africa through Italy to D-Day and the concentration camp at Falkenau. Inescapably scarred by his war experiences (he repeatedly refers to nightmares, an inability to sleep that seemingly plagued him the rest of his long life), he returned to Hollywood after the war and shortly thereafter began directing his own movies, films unique in the studio era for the pungent emotionality and hardness of dialogue and spirit barely containing a deeply empathic humanism. Invariably independent, choosing always to work with low-budgets, B and C level stars in disreputable genres and for (aside from a fruitful collaboration with Darryl Zanuck at Fox) unreliable studios, Fuller carved out a unique niche in the last years of the studio system, with a run of films from 1949-1964 that rank with the greatest works of the American cinema, including masterpieces like The Steel Helmet, Run of the Arrow and Pickup on South Street.
As the studio system collapsed and its B units were replaced by television, Fuller drifted from project to project for the next few decades, while picking up bit-part work in films by a new generation of directors he helped inspire, including Jean-Luc Godard (Pierrot le fou), Dennis Hopper (The Last Movie) and Wim Wenders (in several films). In 1980 he directed possibly the greatest of all World War II films, based on his own experiences, The Big Red One. That was followed by White Dog, a stridently antiracist film that somehow, before it was even released, was perceived as racist and shelved by a petrified Paramount Pictures. The deep hurt and incomprehension felt by Fuller at this great film's treatment is palpable as he recounts the debacle.
All this, as told in Fuller's own words, with his own images (commercial and private) makes for a moving and highly entertaining tribute to a father by a daughter. The celebrity readers are for the most part, excellent, the highlight being an anecdote about Marlene Dietrich read by Wim Wenders, a reunion of four of the cast of The Big Red One (including Mark Hamill) reading excerpts from that section of the book, and readings by filmmakers who've attempted to carry on Fuller's spirit: William Friedkin, Monte Hellman, Buck Henry, James Toback and Joe Dante. The most lovely of Samantha's contributions is a nifty dissolve from one of the most striking images in Fuller's career, a shot from the riotous opening of The Naked Kiss, a close-up of star Constance Towers, to Towers's face in the present as she reads Fuller's words. A true family affair, the film is co-produced by Samuel's widow Christa Lang and the jaunty score is by his nephew Paul Alexander Fuller.
Playing along with A Fuller Life are 16mm prints of two of Fuller's finest films, 1963's Shock Corridor, about a journalist who fakes insanity to get a scoop from inside an asylum and finds himself driven mad by the institution, and 1964's The Naked Kiss, about a prostitute who escapes her awful life to a picture-perfect American suburb only to find deeper horrors underlying that idealized world.
A Fuller Life plays Friday, February 27th – Thursday March 5th.
Shock Corridor plays Monday, March 2nd.
The Naked Kiss plays Wednesday. March 4th.


Yesterday, His Royal Highness Crown Prince Alexander and his wife, Her Royal Highness Crown Princess Katherine of Serbia attended a fundraiser event in Northwood Hills near London. The humanitarian concert at Fairfield Evangelical Church in Northwood Hills was dedicated to raising money for an ambulance for the Toponica Special Psychiatric Hospital near the city of Nis in Serbia.
Toponica Special Psychiatric Hospital's current ambulance is more than 30-years-old, so the hospital needs to get upgraded their equipment so that they may be more efficient. The Serbian royal couple has been pioneers in the effort to improve the health system in Serbia. They have travelled across several countries to raise money.
Before the event, Their Royal Highnesses visited Michael Sobell Hospice to thank them for their support and to learn more about Palliative care. In 2013, Crown Princess Katherine opened the very first Palliative Care Centre in Serbia.
Crown Prince Alexander and Crown Princess Katherine of Serbia during the concert. Photo: THE ROYAL PALACE BELGRADE / Lifeline Humanitarian Organisation.
Her Royal Highness Crown Princess Katherine held a speech at the event.
"I warmly thank Dr Elaine Laycock for her continuous help and devotion for Serbia for over 25 years. Thank you all for being so good in raising funds for the ambulance. My husband and I are delighted to be with you this evening," said the Crown Princess.
Merchant Taylor's Preparatory School Choir, Chen Wang and Nick Aston was among the artists who performed at the charity concert. Merchant Taylor's Preparatory School Choir has previously performed at another charity event at the White Palace in Beograd.
The Serbian royal couple were also in London at the start of February to raise more money. Then, they participated in a charity cocktail and auction at the University Women's Club in London to raise funds and awareness for the treatment of children with disabilities in Serbia.
In 1993, her Royal Highness Crown Princess Katherine founded the Lifeline Humanitarian Organisation with currently has offices in Chicago, New York, Toronto, London and Athens. This organisation, together with "HRH Crown Princess Katherine Foundation" works to collect money for medical equipment that has been delivered to numerous hospitals in Serbia.
If you want to read more about the HRH Crown Princess Katherine Foundation and the Lifeline Humanitarian Organisation, you can do so here.


text:
Recent Insights » WCG Blog » Post-approval Pharmacovigilance: Support Along the Entire Lifecycle of Your Drug
By Angela Pitwood, MBA, Vice President, Pharmacovigilance, WCG
Patient safety doesn't end with regulatory approval. In many ways, approval is just the beginning.
Pharmacovigilance activities conducted after regulatory approval are every bit as important as those conducted during clinical trials. Sponsors know this, but many are nevertheless unprepared for just how much work is involved.
A smaller emerging biopharmaceutical company faces identical post-approval safety and pharmacovigilance requirements as a top-5 pharmaceutical company. The difference is that the larger companies typically have large pharmacovigilance systems in place. However, for an emerging biopharma that may be bringing its first product to market, post-approval pharmacovigilance can be overwhelming.
If you're an emerging biopharma company, you may have been able to manage your pharmacovigilance activities during the clinical trials, but now that the therapy is approved, there may be hundreds of thousands more people taking the drug. Moreover, now there cannot be such a tight control over prescribing, many of the populations now using the drug may not have been fully studied in the clinical trials.
Pharmacovigilance requirements may seem as if they should be simpler once your drug is approved. The data is just as important, but the scope is so much greater, as is the operational burden. Once a drug enters the market, it requires a robust safety system equipped to take a much larger scale of reports—safety reports from wherever in the world the drug is sold as well as from literature surveillance, patient programs and other sources.
This dramatically increases the workload, and smaller companies can't afford a major infrastructure expenditure.
The post-approval pharmacovigilance process is focused on carefully collecting data. But you also need to manage what you're seeing and analyze any safety issues that arise.
Beyond Vigilance: Action
For many sponsors, it makes sense to establish a post-approval safety committee. And again, although larger pharmaceutical companies generally handle this in house, smaller biotech companies may need outside help.
Interpreting inquiries and complaints—with an eye to identifying adverse events that may indicate a rare effect—remains vital especially after approval. Product safety, regulatory compliance and brand integrity are all at stake.
In fact, you may not find rare adverse events until you're in a post-approval setting where many, many more people are taking the drug.
A post-approval safety committee can analyze data in certain populations. If you see something unusual, you can capture it and analyze it before it develops into a serious issue.
It's all part of lifecycle risk management. You need to continue to build the safety profile of your product for the entire time it is on the market. It's a heavy lift, but we can help.
Scalable, Comprehensive, Trusted
Small and emerging biopharmaceutical companies need a customized, scalable turnkey solution that allows them to manage product inquiries from patients and clinicians.
A specialized pharmacovigilance provider such as WCG can provide end-to-end services to support you along the entire lifecycle of your drug. We establish and staff the phone centers, write scripts, design webchats and create automated email responses.
We provide an array of other related services, all of which can be customized to a client's specific situation. Among them:
Implement and maintain a fully validated global safety database for all reports.
Conduct literature surveillance.
Create a full suite of medical information communications.
Review adverse reports from all sources and make the appropriate reports.
Set up safety committees to analyze and assess the data.
Our pharmacovigilance team brings a wealth of combined experience. This means we have the expertise to put processes in place on day 1 and the agility to adapt to a client's changing needs.
To find out more about our pharmacovigilance services, please fill out this form and someone will be in touch.
Ms. Pitwood is responsible for the ongoing development and management of WCG's pharmacovigilance operations. With over 20 years of experience in the pharmaceutical industry, Ms. Pitwood is a healthcare professional who offers her clients the assurance that their safety and pharmacovigilance programs are being managed by a seasoned pharmacovigilance executive with experience in developing, implementing, and leading global safety operations.
Ms. Pitwood has both industry and CRO experience and was formerly Vice President of Drug Safety Surveillance at Pfizer Inc., where she successfully developed and led multiple therapeutic area teams and support functions for the management of adverse event reporting for human health, including all phases of a product life cycle (drugs, vaccines and devices). Ms. Pitwood developed and led these activities using a combination model of in-house staff at three global locations – U.S., Europe, and Asia and three off-shored safety operations vendor sites in the US and Asia.
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redpajama_set_name: RedPajamaCommonCrawl


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Windows 10 - First Impressions
August 21, 2015 - Except for rookie mistakes, the upgrade went smoothly.
It has been years since I took a Windows upgrade so early in the cycle. It has always been my policy to let others absorb all the slings and arrows, then sneak in later armed with foreknowledge and the experience of others. What convinced me to go so early this time is the fact that Windows will now be updated regularly, more or less when Microsoft wants. I decided that getting in early is the only way to start getting informed, if not comfortable, with this particular new normal.
Let me tell you first about the upgrade experience, then share some of my first impressions of Windows 10. My recommendations from my previous article, What About Windows 10?, still stand.
The Upgrades
I upgraded two different types of system, both running Windows 8.1 Pro. One was my wife's little Dell Venue Pro 8 tablet and the other was my late 2014 DIY desktop system (no touch) based on an ASUS motherboard.
In both cases, I relied on the "Get Windows 10" app from Microsoft to inform me about the update and to initiate it. This was my incredibly bone-headed mistake, such a bad error that you need to know about it right off the bat.
Microsoft has, for several versions of Windows, provided an "Advisor" program that would examine your PC and let you know what issue might exist that could prevent a smooth upgrade. I used that utility extensively and recommended it to hundreds of friends, family, and clients. I found the Windows 7 advisor particularly helpful and accurate. The excellence of this program lulled me into a false sense of security, which ultimately led me to believe that the Get Windows 10 app was doing the same kind of assessment when it advised that the system about to be upgraded was "compatible with Windows 10."
Lulled into confidence, I blithely updated both the tablet and my PC without making any other preparations. If I'd had my wits about me, I could have predicted the outcome. In both cases, the computers "broke" in some way. The tablet would no longer turn on after being turned off, requiring hard resets to recover. The PC lost audio, the knowledge that my two big hard drives were joined in a mirror, and as I later learned a couple of less important hardware complications.
In both cases, the solution was a BIOS update followed by some driver updates.
Here's what you need to know: Make these system-specific updates before applying the Windows 10 upgrade no matter what the Get Windows 10 app tells you about the compatibility of your hardware.
Dell has a pretty good support system that made getting the proper updates almost brainless. It doesn't yet work with Microsoft's Edge browser, which meant I had to fuss around a bit because I had already upgraded to Win10; had I done the updates first everything would have been fine. The process at ASUS was less satisfactory; perhaps ASUS presumes a higher degree of systems expertise in its customers but this is one time I wish ASUS was Dell. ASUS leaves a lot of things unsaid, such as whether the most current BIOS for my board was to be used only with 5th-generation Intel CPUs or could be used with 4th-generation, like mine. ASUS has huge inconsistency in file naming, which made the task even more confusing.
The good news is that once these hardware and driver updates were made, everything ran smoothly.
My RAID problem was alarming. After Windows 10 was installed, the two drives appeared as two drives, with different drive letters, instead as one drive. I ultimately had to use Intel's Rapid Storage Technology (IRST) app to rebuild the mirror by telling IRST that the contents of one of the drives was good. It's not clear to me if I could have avoided this problem or not, nor whether recovering a RAID 5 drive would have been as easy. After some research, my best guess is that I should have upgraded IRST first, then BIOS, and then Windows 10. If you have RAID in your system, check it out more carefully than I did.
My boot drive (C:) is an SSD. Because it is only 240GB, I have Windows set to place most user files on the D: drive, the mirror. Had I lost the data, the recovery would have been very, very messy. I should have had a full backup of everything, and I didn't. Word to the wise.
There's one other thing I should have done before the upgrade - uninstall Start8, my replacement start menu app. When I was faced with Windows 10 for the first time, I didn't see the new Windows 10 menu and was momentarily confused. Once Start8 was gone, the new menu appeared.
Now for some early observations about Windows 10. If you read my earlier article, you know I complained about three things in Windows 8 - the Start Menu, the Start Screen, and "Metro" (now called "Modern") apps. I'll explain my view on all those points but before I do that, let me give you some overall impressions.
I looked for problems with performance. I found none. I felt (but did not measure technically) that Windows 10 was a little peppier. I am wondering why, but I'll take it.
I looked for problems with compatibility. As I said in my earlier article, I expected everything that ran in Windows 8 to run in Windows 10 and that does seem to be the case. The only compatibility problems I had were due to not getting the hardware updates handled first. But even then, Windows 10 still ran.
My biggest gripe is with the user interface. Microsoft's absurd journey into flatland continues. Microsoft has worked so hard on UI for so long, and now this junk. Just look at the Windows 10 calculator. I can barely express how awful this is - low contrast, no delineation of functional areas, no definition of buttons, nothing like the rich graphics from Windows past. I'm not suggesting that the calculator has to look exactly like a physical calculator but I am saying outright that Microsoft has gone off the deep end in making everything flat. It's not just this one app either; I think Office 2013 stinks where the UI is concerned, with exactly the same problems.
Greatness, decades of research, squandered. (No knighthoods for Microsoft's designers, I guess.)
Start Menu / Start Screen
These two are lumped together because that's exactly what Microsoft has done in Windows 10. I'm just getting in to this and it's only been a few days but I'm feeling the loss of the Windows 7 start menu again.
There's no question that this new start menu is an improvement but that's like saying an oasis is an improvement on the desert. My point is that comparing the Windows 10 start menu to Windows 8 is comparing something to nothing, so the comparison must be between Windows 10 and Windows 7.
On the tablet I'm more or less satisfied. I said before that I liked the tiled interface for touch and that remains. After nearly two years using the tablet I've adapted to a host of gestures that no longer work as expected. Retraining is necessary. But that's all it is, just some more practice and adaptation.
On the desktop I'm not as happy. The new menu is billed as a blending of Windows 7 and Windows 8 but as far as I'm concerned nothing more than lip service is being given to Windows 7. The ability to customize is not what I thought it would be. For example, pinning an item to start pins a tile, not an entry in the left side of the menu as with Windows 7. I'm not happy with the move of the search box to the bottom taskbar and out of the start menu. As things stand today, I'm seriously considering buying Start10 from Stardock. It's just $5 and I did like Start8, so switching right away is tempting but in fairness I'll give it a few weeks before I commit.
Although the regular Windows start menu has always been good, I make excellent use of the bottom taskbar. I pin my most important apps to it, such as the key productivity programs like Word and Excel and most of the development tools I use in Web development. A key to the taskbar's productivity has been the right-click, which brings up a context menu for that app. The menu contains a jump list of recent files but, most important, an entry that launches a new instance of the app. After the Windows 10 install, that menu was not present, which distressed me greatly. A few days later those menus started showing up again. I don't know if this was a bug that got fixed with a patch or if it just took Windows 10 a few days to get its bearings. Either way, I'm glad the taskbar is back to normal. The menus are slightly improved, with a little bit of organization.
One of the great mysteries with Windows 7 was what happened to the Show Desktop icon that was always present in the Quick Launch area of the bottom taskbar. It moved to a little unmarked zone at the far right of the toolbar, just after the time display and without the icon. It's still there in Windows 10, but it got a lot smaller. Thank goodness there won't be a Windows 11 or it would vanish forever.
Metro/Modern Apps & the Desktop
I am pleased with the direction here. You'll recall that my complaint was that a Modern app could not be resized but always took full screen. Great for tablets, horrible for the desktop. That's been changed. So far, all the Modern apps I've tried can be resized, returning the desktop experience to that preferred by, I'm absolutely confident, tens of millions of desktop users. The improvement extends to tablets, where the top bar of a Modern app can be dragged down to expose the close button in the upper right, which allows apps to be closed on tablets without resorting to the annoying process of getting Task Manager running. Now I can resize and close on demand, just what the dedicated desktop user wants. Kudos to Microsoft for listening to our complaints.
And I can once again play games while watching mindless videos. Bliss.
The Bad - Microsoft Edge
I've had no problems with the new Edge browser in terms of rendering pages. There have been some outliers and when I looked at the page code I found some old coding practices that clearly led to the problems. The Dell problem I mentioned above was that its automatic driver detection code would not run, suggesting that Dell has not completed the necessary upgrade of its site (or that something is not yet finished in Edge, to be fair to Dell). Overall, I'm not having any problem at the sites I frequent.
Where Edge falls flat is its user interface. Again, Microsoft fails us.
For the last decade, Microsoft has been derided for endless problems with Internet Explorer. Some of these, such as compliance with Web standards or slowness to add features like tabbed browsing, are deserved. Most others I've never agreed with. Folks forget what got Microsoft into the browser business in the first place, unseating Netscape in the process. It was convenience features, a vastly improved UI. In spite of other problems, IE4, 5, and 6 catapulted Microsoft into browser dominance. Had Microsoft's technical underpinnings for IE been better, it would have been much harder for others to gain share. Those others - Apple, Google, Mozilla, Opera - all adopted many of Microsoft's UI advances and improved upon them, while delivering a better technical product in the bargain.
With Edge, Microsoft has tossed whatever UI edge it had away. Edge looks (and unfortunately acts) like Chrome. How far the fall, Microsoft following Google.
I would probably not be so angry about all this except that Microsoft changed a keystroke sequence that I use every day. It has always been the case that Ctrl+Click on a link opened a new tab. But that's all it did; the focus remained on the tab where you clicked. Ctrl+Shift+Click opens a new tab and switches to that tab. Firefox originated an option called "When I open a link in a new tab, switch to it immediately" that effectively made both keyboard shortcuts behave the same, switching focus to the new tab. IE adopted that same option when it finally gained tabs. Chrome does not have and has never had that option, which I consider idiotic. But now Edge does not have it, either.
Perhaps I'm being petty, but try it. Is it easier to hold one key down when clicking or two? The answer is pretty clear, so I've been using Ctrl-Click for as long as Firefox has been around to open a tab and switch to it. The absence of this tiny UI feature is a huge reason I don't use Chrome (I have other more weighty ones). It's a huge reason I'm not happy with Edge.
Just to make sure you don't think I'm crazy, I do recognize that the tiny spark of this one omission ignited a full blaze in me. But it also made me look more closely at Edge, hoping to be overwhelmed by other exciting new features. Didn't happen. There's more, and there's worse. I plan to tell you more about Edge in the near future. Thank goodness IE11 remains available - at least Microsoft got that right.
Because I have to force myself to use Edge, I am. I've left the default for links set to Edge so that if I click a link from an email, for example, it will be Edge that comes up, not IE11. That way I'll constantly be exposed to Edge, good or bad. But when I launch a browser myself, it will be IE11.
It's too soon to draw broad conclusions. Except for the UI issues, my typical workflow has not been substantially altered. Some of the UI issues will smooth out over time as I adapt. Program compatibility back to Windows 8 is, as I expected, good.
Thus my recommendations from the earlier article stand. Take the upgrade barring any obstacles. And for heaven's sake, make the systems upgrades first - don't be like that other me.
Tags: Microsoft, Windows, Windows 10
Windows 10 Driving Mode
February 26, 2017 (Windows, Windows 10, Windows Phone)
All Your Files Are Exactly Where You Left Them
April 6, 2016 (Microsoft, Windows)
The Dull Edge
December 11, 2015 (Browsers, Edge, Microsoft, Windows)
The New Lumia Phones
November 12, 2015 (Smartphones, Windows)
How to Buy a Tablet
November 10, 2015 (Apple, Microsoft, tablet, Windows)
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