Vasopressin versus epinephrine during cardiopulmonary resuscitation of asphyxiated newborns: A study protocol for a prospective, cluster, open label, single-center, randomized controlled phase 2 trial - The VERSE-Trial.

Introduction: Current neonatal resuscitation guidelines recommend the use of epinephrine during neonatal cardiopulmonary resuscitation (CPR). However, newborns receiving epinephrine continue to have high rates of mortality and neurodevelopmental disability. The infrequent need for neonatal CPR, coupled with an inability to consistently anticipate which newborn infants are at risk of requiring CPR, explains the lack of high-quality evidence (i.e., large randomized clinical trials) to better guide healthcare providers in their resuscitative effort. Therefore, we need neonatal data to determine the optimal vasopressor therapy during neonatal CPR. The current pilot trial will examine the efficacy of vasopressin versus epinephrine during CPR of asphyxiated newborn infants. Methods and analysis: The trial will be a prospective, cluster, open label, single-center, randomized controlled trial on two alternative cardiovascular supportive medications. This study will assess the primary outcome of time to return of spontaneous circulation (ROSC) in newborns requiring CPR in the delivery room who were treated with either vasopressin (intervention) or epinephrine (control). Secondary outcomes such as infant mortality and other clinical outcome measures will also be collected. An estimated 20 newborns will be recruited, and comparisons will be made between asphyxiated infants treated with either drugs. Ethics and dissemination: This study has been approved by the Research Ethics Board at the University of Alberta (June 16, 2023). Study findings will be published in peer-reviewed journals, presented at conferences, and communicated to relevant participants and stakeholders.Trial registration: ClinicalTrial.gov Identifier: NCT05738148. Registered February 21, 2023.

Hypoxia - Reoxygenation in neonatal cardiac arrest: Results from experimental models.

In this review, we summarize the results of studies that investigated the effects of hypoxia and reoxygenation in cardiac arrest, including the use of different fractions of inspired oxygen, in neonatal animals. The studies were heterogenous in terms of anaesthetic regimens, and definitions of cardiac arrest and circulatory recovery. Cardiopulmonary resuscitation with 100% oxygen increased oxidative stress in maturing rats. Studies in fetal/neonatal lambs and post-transitional neonatal piglets indicate no consistent differences between ventilation with 21% vs. 100% oxygen with regards to recovery times, oxygen damage or adverse events. If 21% oxygen is as effective as 100% oxygen in newborn infants with cardiac arrest requiring chest compression, the use of 21% instead of 100% oxygen could reduce morbidity and mortality in asphyxiated infants. Unanswered questions include what is the most optimal cerebral oxygen delivery during reperfusion, as well as oxygenation targets after return of spontaneous circulation.

Novel interventions to reduce oxidative-stress related brain injury in neonatal asphyxia.

Perinatal asphyxia-induced brain injury may present as hypoxic-ischemic encephalopathy in the neonatal period, and disability including cerebral palsy in the long term. The brain injury is secondary to both the hypoxic-ischemic event and the reoxygenation-reperfusion following resuscitation. Early events in the cascade of brain injury can be classified as either inflammation or oxidative stress through the generation of free radicals. The objective of this paper is to present efforts that have been made to limit the oxidative stress associated with hypoxic-ischemic encephalopathy. In the acute phase of ischemia/hypoxia and reperfusion/reoxygenation, the outcomes of asphyxiated infants can be improved by optimizing the initial delivery room stabilization. Interventions include limiting oxygen exposure, and shortening the time to return of spontaneous circulation through improved methods for supporting hemodynamics and ventilation. Allopurinol, melatonin, noble gases such as xenon and argon, and magnesium administration also target the acute injury phase. Therapeutic hypothermia, N-acetylcysteine2-iminobiotin, remote ischemic postconditioning, cannabinoids and doxycycline target the subacute phase. Erythropoietin, mesenchymal stem cells, topiramate and memantine could potentially limit injury in the repair phase after asphyxia. To limit the injurious biochemical processes during the different stages of brain injury, determination of the stage of injury in any particular infant remains essential. Currently, therapeutic hypothermia is the only established treatment in the subacute phase of asphyxia-induced brain injury. The effects and side effects of oxidative stress reducing/limiting medications may however be difficult to predict in infants during therapeutic hypothermia. Future neuroprotection in asphyxiated infants may indeed include a combination of therapies. Challenges include timing, dosing and administration route for each neuroprotectant.

Effects of different durations of sustained inflation during cardiopulmonary resuscitation on return of spontaneous circulation and hemodynamic recovery in severely asphyxiated piglets.

OBJECTIVE: We previously demonstrated that sustained inflation (SI) during chest compression (CC) significantly reduces time to return of spontaneous circulation (ROSC) when compared to 3:1 compression:ventilation (C:V) ratio during neonatal resuscitation. However, the optimal length of SI during CC to improve ROSC and hemodynamic recovery in severely asphyxiated piglets is unknown. AIM: To examine if different lengths of SI will improve ROSC and hemodynamic recovery in severely asphyxiated piglets. INTERVENTION AND MEASUREMENTS: Thirty newborn piglets (1-3 days) were anesthetized, intubated, instrumented and exposed to 30-min normocapnic hypoxia followed by asphyxia. Piglets were randomized into four groups: 3:1 C:V (n = 8), CC with an SI duration of either 20 s (CC+SI 20) (n = 8) or 60 s (CC+SI 60) (n = 8), and a sham group (n = 6). Cardiac function, carotid blood flow, cerebral and renal oxygenation as well as respiratory parameters were continuously recorded throughout the experiment. MAIN RESULTS: When compared with 3:1 group, both CC+SI 20 and CC+SI 60 groups had significantly shorter ROSC time (p = 0.002). All three intervention groups had similar hemodynamic recovery by the end of 4 h observation period. There was no difference in lung injury markers among all experimental groups. However, when compared to the sham group, the concentrations of IL-6 (thalamus) and IL-6 + IL-8 (frontoparietal cortex) of the 3:1 C:V group were significantly higher, respectively. CONCLUSIONS: Even though relatively less animals achieved ROSC, CC during SI significantly improved ROSC time compared to 3:1 C:V in asphyxiated newborn piglets. However, there was no difference in ROSC characteristics and hemodynamic recovery between two CC+SI groups.

Tidal volume delivery during continuous chest compressions and sustained inflation.

OBJECTIVE: To determine the distending pressure needed to achieve sufficient tidal volume (VT) delivery during continuous chest compressions (CC) superimposed by sustained inflation (SI) (CC+SI). DESIGN: Randomised animal/manikin trial. SETTING: University laboratory. SUBJECTS: Cadaver piglets/manikin. INTERVENTIONS: SI distending pressures of 5, 10, 15, 20, 25 and 30 cm H2O were delivered in random order during CC+SI for 2 min each. MAIN OUTCOME MEASURES: VT, gas flow and airway pressure. Spearman's r for distending pressure and VT. RESULTS: Distending pressure and VT correlated in cadaver piglets (r=0.83, p<0.001), manikin (r=0.98, p<0.001) and combined data (r=0.49, p<0.001). VT was delivered during chest recoil during CC in both models. In cadaver piglets, a distending pressure ∼25 cm H2O was needed to achieve an adequate VT. CONCLUSIONS: Chest recoil generates VT depending on an adequate distending pressure. This has previously been demonstrated in adult animals. A pressure of ∼25 cm H2O is needed to achieve an adequate VT delivery.

Assessment of endotracheal tube placement in newborn infants: a randomized controlled trial.

OBJECTIVE: International resuscitation guidelines recommend clinical assessment and exhaled CO2 to confirm tube placement immediately after intubation. However, exhaled CO2 devices can display false negative results. In comparison, any respiratory function monitor can be used to measure and display gas flow in and out of an endotracheal tube. However, neither method has been examined in detail. We hypothesized that a flow sensor would improve the assessment of tracheal vs esophageal tube placement in neonates with a higher success rate and a shorter time to tube placement confirmation when compared with the use of a quantitative end-tidal CO2 (ETCO2) detector. STUDY DESIGN: Between December 2013 and September 2014, preterm and term infants requiring endotracheal intubation were eligible for inclusion and randomly allocated to either ETCO2 ('ETCO2 group') or flow sensor ('flow sensor group'). All infants were analyzed according to their group at randomization (that is, analysis was by intention-to-treat). RESULT: During the study period, a total of 110 infants (n=55 for each group) were randomized. Successful endotracheal tube placements were correctly identified in 100% of cases by the flow sensor compared with 72% of cases with the ETCO2 detector within 10 inflations (P<0.05). The median (interquartile range) number of inflations needed to identify successful tube placement was significantly lower in the flow sensor group with 2 (1 to 3) inflations vs 8 (6 to 10) inflations with the ETCO2 detector (P<0.001). CONCLUSION: A flow sensor would improve the assessment of successful endotracheal tube placement with a higher success rate and a shorter time compared with an ETCO2 detector.

Rescuer fatigue during simulated neonatal cardiopulmonary resuscitation.

OBJECTIVE: To assess development of fatigue during chest compressions (CCs) in simulated neonatal cardiopulmonary resuscitation (CPR). STUDY DESIGN: Prospective randomized manikin crossover study. Thirty neonatal healthcare professionals who successfully completed the Neonatal Resuscitation Program performed CPR using (i) 3:1 compression:ventilation (C:V) ratio, (ii) continuous CC with asynchronous ventilation (CCaV) at a rate of 90 CC per min and (iii) CCaV at 120 CC per min for a duration of 10 min on a neonatal manikin. Changes in peak pressure (a surrogate of fatigue) and CC rate were continuously recorded and fatigue among groups was compared. Participants were blinded to pressure tracings and asked to rate their level of comfort and fatigue for each CPR trial. RESULT: Compared with baseline, a significant decrease in peak pressure was observed after 72, 96 and 156 s in group CCaV-120, CCaV-90 and 3:1 C:V, respectively. CC depth decreased by 50% within the first 3 min during CCaV-120, 30% during CCaV-90 and 20% during 3:1 C:V. Moreover, 3:1 C:V and CCaV were similarly preferred by healthcare professionals. CONCLUSION: Similarly, 3:1 C:V and CCaV CPR were also fatiguing. We recommend that rescuers should switch after every second cycle of heart rate assessment during neonatal CPR.

Mask ventilation with two different face masks in the delivery room for preterm infants: a randomized controlled trial.

BACKGROUND: If an infant fails to initiate spontaneous breathing after birth, international guidelines recommend a positive pressure ventilation (PPV). However, PPV by face mask is frequently inadequate because of leak between the face and mask. Despite a variety of available face masks, none have been prospectively compared in a randomized fashion. We aimed to evaluate and compare leak between two commercially available round face masks (Fisher & Paykel (F&P) and Laerdal) in preterm infants <33 weeks gestational age in the delivery room. METHODS: Infants born at the Royal Alexandra Hospital from April to September 2013 at <33 weeks gestational age who received mask PPV in the delivery room routinely had a flow sensor placed between the mask and T-piece resuscitator. Infants were randomly assigned to receive PPV with either a F&P or Laerdal face mask. All resuscitators were trained in the use of both face masks. We compared mask leak, airway pressures, tidal volume and ventilation rate between the two groups. RESULTS: Fifty-six preterm infants (n=28 in each group) were enrolled; mean±s.d. gestational age 28±3 weeks; birth weight 1210±448 g; and 30 (52%) were male. Apgar scores at 1 and 5 min were 5±3 and 7±2, respectively. Infants randomized to the F&P face mask and Laerdal face mask had similar mask leak (30 (25-38) versus 35 (24-46)%, median (interquartile range), respectively, P=0.40) and tidal volume (7.1 (4.9-8.9) versus 6.6 (5.2-8.9) ml kg(-1), P=0.69) during PPV. There were no significant differences in ventilation rate, inflation time or airway pressures between groups. CONCLUSION: The use of either face mask during PPV in the delivery room yields similar mask leak in preterm infants <33 weeks gestational age.

Management of hypotension in preterm infants (The HIP Trial): a randomised controlled trial of hypotension management in extremely low gestational age newborns.

BACKGROUND: Extremely preterm babies (delivered at <28 completed weeks of gestation) are frequently diagnosed with hypotension and treated with inotropic and pressor drugs in the immediate postnatal period. Dopamine is the most commonly used first-line drug. Babies who are treated for hypotension more frequently sustain brain injury, have long-term disability or die compared to those who are not. Despite the widespread use of drugs to treat hypotension in such infants, evidence for efficacy is lacking, and the effect of these agents on long-term outcomes is unknown. HYPOTHESIS: In extremely preterm babies, restricting the use of dopamine when mean blood pressure (BP) values fall below a nominal threshold and using clinical criteria to determine escalation of support ('restricted' approach) will result in improved neonatal and longer-term developmental outcomes. RESEARCH PLAN: In an international multi-centre randomised trial, 830 infants born at <28 weeks of gestation, and within 72 h of birth, will be allocated to 1 of 2 alternative treatment options (dopamine vs. restricted approach) to determine the better strategy for the management of BP, using a conventional threshold to commence treatment. The first co-primary outcome of survival without brain injury will be determined at 36 weeks' postmenstrual age and the second co-primary outcome (survival without neurodevelopmental disability) will be assessed at 2 years of age, corrected for prematurity. DISCUSSION: It is essential that appropriately designed trials be performed to define the most appropriate management strategies for managing low BP in extremely preterm babies.

Differential hemodynamic effects of levosimendan in a porcine model of neonatal hypoxia-reoxygenation.

BACKGROUND: Neonatal asphyxia can be complicated by myocardial dysfunction with secondary alterations in pulmonary and regional hemodynamics. Levosimendan is a calcium-sensitizing inotrope that may support cardiac output, but little is known regarding its differential hemodynamic effects in asphyxiated neonates. METHODS: Mixed breed piglets (1-4 days old, weight 1.6-2.3 kg) were acutely instrumented. Normocapnic alveolar hypoxia (10-15% oxygen) was induced for 2 h, followed by reoxygenation with 100% (1 h) and then 21% oxygen (3 h). At 2 h of reoxygenation, after volume loading (Ringer's lactate 10 ml/kg), either levosimendan (0.1 or 0.2 µg/kg/min) or D(5)W (placebo) was infused for 2 h in a blinded, block-randomized fashion (n = 7-8/group). The systemic, pulmonary and regional (carotid, superior mesenteric and renal) hemodynamics were compared. RESULTS: At 0.1 and 0.2 µg/kg/min, levosimendan significantly increased cardiac output (121 and 123% of pretreatment, respectively) and heart rate, and decreased systemic vascular resistance without causing hypotension. Pulmonary arterial pressure and estimated pulmonary vascular resistance were significantly increased from pretreatment baseline in 0.1 but not 0.2 µg/kg/min levosimendan. Levosimendan infusion had no effects on regional hemodynamics. Myocardial efficiency but not oxygen consumption increased with 0.1 µg/kg/min levosimendan without significant effects on plasma troponin and myocardial lactate levels. CONCLUSIONS: In newborn piglets following hypoxia-reoxygenation injury, levosimendan improves cardiac output but has no marked effects in carotid, superior mesenteric and renal perfusion. It appears that various doses of levosimendan increase the cardiac output through different mechanisms. Further investigations are needed to examine the effectiveness of levosimendan as a cardiovascular supportive therapy either alone or in conjunction with other inotropes in asphyxiated neonates.

Application of BAX system, Tecra Unique Salmonella test, and a conventional culture method for the detection of Salmonella in ready-to-eat and raw foods.

AIMS: To compare the BAX system, the Tecra Unique Salmonella test, and a conventional culture method for the detection of Salmonella in various foods. METHODS AND RESULTS: Ready-to-eat and raw foods were inoculated with Salmonella serotype Typhimurium, Salmonella serotype Enteritidis, Salmonella serotype Typhi, or Salmonella serotype Derby. Incubated pre-enrichment cultures were examined using the BAX system, the Tecra Unique Salmonella test, and a conventional culture method. Salmonella could be detected in all ready-to-eat food samples inoculated with S. Typhimurium, S. Enteritidis, or S. Derby, with any of the three test methods. However, false negatives were obtained with the Tecra test and the culture method when samples with higher background flora were inoculated with S. Typhi. Sensitivity test results suggested the two rapid tests performed as well as the culture method in the detection of 10(1) CFU of S. Typhimurium in 25-g cooked or raw food. CONCLUSIONS: The BAX system and the Tecra Unique Salmonella test demonstrated results comparable with those of the culture method in the detection of Salmonella serotypes used except S. Typhi. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first evaluation of the BAX system, the Tecra Unique Salmonella test, and a culture method in the detection of Salmonella in a variety of western and oriental foods.

Evaluation of two real-time polymerase chain reaction pathogen detection kits for Salmonella spp. in food.

AIMS: To evaluate the LightCycler Salmonella Detection Kit and the TaqMan Salmonella Gold Detection and Quantitation Kit for the real-time PCR detection of Salmonella in various food samples. METHODS AND RESULTS: Ready-to-eat foods and raw food samples were artificially contaminated with Salmonella serotypes. In the specificity test, bacterial DNA extracted from sample pre-enrichment culture was analysed with the detection kits performed respectively on the LightCycler Instrument or the ABI Prism 7000 Sequence Detection System. No false-positive or false-negative results were obtained, although the LightCycler system generated invalid PCR results on two occasions. In the sensitivity test using the LightCycler system, Salmonella could be detected in pre-enrichment cultures of 25-g samples inoculated with as low as 1.5 x 10(3) CFU (depending on food type), and false-negative results were obtained for samples with low inoculum levels. CONCLUSIONS: Two commercial kits for real-time PCR detection of Salmonella were evaluated. SIGNIFICANCE AND IMPACT OF THE STUDY: Evaluation using more food types and matrices, and foods that contain low number of Salmonella or high number of other competing bacteria, is needed before adopting the real-time PCR technique for routine food tests.

Inhaled nitric oxide inhibits the release of matrix metalloproteinase-2, but not platelet activation, during extracorporeal membrane oxygenation in adult rabbits.

BACKGROUND/PURPOSE: In neonates receiving extracorporeal membrane oxygenation (ECMO), platelet activation and dysfunction occur with the release of matrix metalloproteinase (MMP)-2, which stimulates platelet aggregation. Because inhaled nitric oxide (NO) reduces pulmonary hypertension and inhibits platelet aggregation, the authors examined the effects of inhaled NO on platelet activation induced by ECMO. METHODS: Ten adult white New Zealand rabbits were instrumented for ECMO and assigned randomly to receive either inhaled NO at 40 ppm or 30% oxygen for 1 hour before ECMO and continued for 4 hours after starting ECMO. Platelet counts, collagen-induced platelet aggregation ex vivo, plasma MMP-2, and MMP-9 activities were measured. RESULTS: (1) ECMO caused thrombocytopenia, decreased platelet aggregation, and increased plasma MMP-2 and MMP-9 activities in controls. (2) Inhaled NO inhibited platelet aggregation before ECMO but did not affect the ECMO-induced thrombocytopenia and platelet activation. (3) Inhaled NO significantly abolished the ECMO-induced increase in plasma MMP-2 but not MMP-9 activities. CONCLUSIONS: Although inhaled NO did not inhibit the platelet activation during ECMO in adult rabbits, it attenuated the increase in plasma MMP-2 activity that may be important for neonates treated with ECMO.