The use of biological agents in pregnant women affected by autoimmune disorders: Why we need more research of this neglected area.

Women of childbearing age are largely affected by several autoimmune disorders (the estimates range between 1.5 and 10 per 10,000). The increasing number of effective biological agents has dramatically revolutionized the treatment of these clinical conditions, ameliorating the patient's quality of life. The use of these agents by women during pregnancy is growing to ensure the disease activity control and avoid adverse health outcomes. However, for many newer biological agents, the degree of information concerning their use in pregnancy is often incomplete to perform a conclusive risk assessment on fetal and maternal health given the exclusion of this specific population from pharmacological clinical trials. More recently, the COVID-19 pandemic has confirmed the unacceptable inequities of pharmacological research and medical treatment for pregnant and lactating women, exacerbating the need for filling the gaps of quantitative and qualitative pharmacology data in this sensitive population. ere we summarize (i) what is already known about safety and effectiveness of biological agents in this understudied population (with specific focus on pregnancy-related health outcomes), and what we are going to learn from the on-going studies among pregnant women treated with biological agents; (ii) the methodological and ethical considerations that characterize the pharmacological research in pregnancy, also discussing emerging evidence on the use of therapeutic drug monitoring (TDM) in this clinical setting.

Herpes zoster and simplex reactivation following COVID-19 vaccination: new insights from a vaccine adverse event reporting system (VAERS) database analysis.

BACKGROUND: A few cases of Herpes Zoster and Simplex reactivation following COVID-19 immunization have been recently described, but the real extent of this suspected adverse event has not been elucidated yet. METHODS: We performed a nested case/control study by using the U.S. Vaccine Adverse Event Reporting System database. We carried out a case-level clinical review of all Herpes reactivation cases following the administration of COVID-19 vaccines. For cases and controls, significance was set at P = 0.05, differential risk of reporting was assessed for each vaccine as reporting odds ratio and incidence was estimated based on the total number of vaccine doses administered. RESULTS: Of 6,195 cases included in the analysis (5,934 and 273 reporting Herpes Zoster and Herpes Simplex, respectively) over 90% were non-serious. We found a slightly higher risk of reporting both for Zoster (ROR = 1.49) and Simplex (ROR = 1.51) infections following the Pfizer-BioNTech vaccine. The estimated incidence was approximately 0.7/100,000 and 0.03/100,000 for Zoster and Simplex, respectively. CONCLUSIONS: The paucity of cases (almost all of non-serious nature) makes the potential occurrence of this adverse effect negligible from clinical standpoints, thus supporting the good safety profile of the COVID-19 vaccination, which remains strongly recommended.

Ocular ultrasound to detect intracranial hypertension in trauma patients.

BACKGROUND: Increases in intracranial pressure (ICP) after head trauma require a rapid recognition to allow for adequate treatments. The aim of this study was to determine whether dilation of the optic nerve sheath, as detected by ocular ultrasound at the bedside, could reliably identify increases in ICP assessed with an intraparenchymal probe in adult head trauma patients. METHODS: Eleven head trauma injured adult patients admitted to the intensive care unit with a Glasgow Coma Scale score ≤8, with cerebral contusion confirmed by computed tomography scan, and that required invasive ICP monitoring, were enrolled in the study. ICP values ≤20 mm Hg were considered as normal. Patients with acute or chronic ocular lesion were excluded. Ten nontrauma intensive care unit patients, with no ICP monitoring, were enrolled as control group. Invasive arterial pressure was monitored, and optic nerve sheath diameter (ONSD) was assessed by ocular ultrasound in all the patients. RESULTS: Head trauma patients without intracranial hypertension had ONSD values, assessed by ultrasound, equivalent to those measured in control patients (5.52 mm ± 0.36 mm vs. 5.51 mm ± 0.32 mm). ONSD, instead, significantly increased to 7.0 mm ± 0.58 mm, when ICP rose in value to >20 mm Hg (p < 0.0001 vs. normal ICP and control). ONSD values were significantly correlated to ICP values (r = 0.74, p < 0.001). CONCLUSIONS: When ICP was higher than 20 mm Hg, the ONSD diameter increased, whereas when the ICP was below 20 mm Hg, the ONSD returned to values equivalent to those assessed in control nontrauma patients. Accordingly, ocular ultrasound may be considered as a good alternative for a rapid indirect evaluation of head trauma patients' ICP.

Preliminary evidence on the safety profile of BNT162b2 (Comirnaty): new insights from data analysis in EudraVigilance and adverse reaction reports from an Italian health facility.

The first vaccine against SARS-CoV-2 made available in Italy has been BNT162b2, the two-dose mRNA-based vaccine developed by Pfizer-BioNTech. The ASST Fatebenefratelli-Sacco hospital is located in one of the areas most affected by the pandemic, and to date over 2000 healthcare professionals have been injected with both vaccine doses. We have collected all spontaneous safety reports in which BNT162b2 was designated as the possible cause. We also have carried out a descriptive analysis of reports submitted in EudraVigilance in the same time-frame and compared our findings with those observed in clinical trials. We have identified several new and unexpected adverse reactions that will be helpful for reviewing the safety profile defined in the Summary of Product Characteristics for this vaccine.

Buccal capnometry to guide management of massive blood loss.

In both clinical and experimental settings, tissue P(CO2) measured in the oral mucosa is a practical and reliable measurement of the severity of hypoperfusion. We hypothesized that a threshold level of buccal tissue P(CO2) (P(CO2) BU)) would prognosticate the effects of volume repletion on survival. Twenty pentobarbital-anesthetized Sprague-Dawley male breeder rats, each weighing approximately 0.5 kg, were randomly assigned to one of four groups. Animals were bled over an interval of 30 min in amounts estimated to be 25, 30, 35, or 40% of total blood volume. One-half hour after the completion of bleeding, each animal received an infusion of Ringer lactate solution over the ensuing 30 min in amounts equivalent to two times the volume of blood loss. P(CO2) BU) was measured continuously with an optical P(CO2) sensor applied noninvasively to the mucosa of the left cheek. Arterial pressure and end-tidal CO2 were measured over the same interval. Neurological deficit and 72-h survival were recorded. Aortic pressures were restored to near baseline values for each of the four groups after fluid resuscitation. This contrasted with the improvement of P(CO2) BU), which differentiated between animals with short and long durations of postintervention survival. After electrolyte fluid resuscitation in rats subjected to rapid bleeding, noninvasive measurement of P(CO2) BU) was predictive of outcomes. Neither noninvasive end-tidal P(CO2) nor invasive aortic pressure measurements achieved such discrimination. Accordingly, P(CO2) BU) fulfills the criterion of a noninvasive and reliable measurement to guide fluid management of hemorrhagic shock.

Challenging the rationale of three sequential shocks for defibrillation.

The 2000 guidelines for cardiopulmonary resuscitation (CPR) recommend up to three sequential shocks for persistent ventricular fibrillation (VF). We hypothesized that the time consumed for repetitive rhythm analyses and recharging of the capacitor compromises the success of the second and third shock of each sequence. In 60 domestic pigs, VF was electrically induced and untreated for 7 min. After 1 min of CPR, which includes precordial compression and ventilation, up to three sequential shocks were delivered. All animals were resuscitated. For purposes of the present study we determined the outcomes of the first, the second, and the third shock of each sequence during attempted defibrillation. Our criterion of success was the restoration of spontaneous circulation (ROSC). Forty-eight of the 60 animals (80%) attained ROSC after the first shock, 9/60 (15%) after the second shock, and only 3/60 (5%) after the third shock. In confirmation of the earlier observations, ROSC was highly predictive when the coronary perfusion pressure (CPP) exceeded 12 mmHg and end-tidal CO(2) (ETCO(2)) exceeded 11 mmHg. However, these criteria were never achieved after the second shock. The present study supports the rationale of delivering only a single shock, or at the most two shocks, prior to resuming chest compression, to re-establish the threshold levels of CPP and ETCO(2) before delivery of a subsequent electrical shock.

Individual patient data systematic review and meta-analysis of optic nerve sheath diameter ultrasonography for detecting raised intracranial pressure: protocol of the ONSD research group.

BACKGROUND: The purpose of the optic nerve sheath diameter (ONSD) research group project is to establish an individual patient-level database from high quality studies of ONSD ultrasonography for the detection of raised intracranial pressure (ICP), and to perform a systematic review and an individual patient data meta-analysis (IPDMA), which will provide a cutoff value to help physicians making decisions and encourage further research. Previous meta-analyses were able to assess the diagnostic accuracy of ONSD ultrasonography in detecting raised ICP but failed to determine a precise cutoff value. Thus, the ONSD research group was founded to synthesize data from several recent studies on the subject and to provide evidence on the diagnostic accuracy of ONSD ultrasonography in detecting raised ICP. METHODS: This IPDMA will be conducted in different phases. First, we will systematically search for eligible studies. To be eligible, studies must have compared ONSD ultrasonography to invasive intracranial devices, the current reference standard for diagnosing raised ICP. Subsequently, we will assess the quality of studies included based on the QUADAS-2 tool, and then collect and validate individual patient data. The objectives of the primary analyses will be to assess the diagnostic accuracy of ONSD ultrasonography and to determine a precise cutoff value for detecting raised ICP. Secondly, we will construct a logistic regression model to assess whether patient and study characteristics influence diagnostic accuracy. DISCUSSION: We believe that this IPD MA will provide the most reliable basis for the assessment of diagnostic accuracy of ONSD ultrasonography for detecting raised ICP and to provide a cutoff value. We also hope that the creation of the ONSD research group will encourage further study. TRIAL REGISTRATION: PROSPERO registration number: CRD42012003072.

Buccal capnometry for quantitating the severity of hemorrhagic shock.

We have recently demonstrated that measurement of buccal mucosal PCO2 (PBUCO2) is a reliable alternative to sublingual mucosal PCO2 for measuring the severity of hemorrhagic shock. We hypothesized that measurement of PBUCO2 would serve as a continuous and a more sensitive and specific measurement for predicting survival during hemorrhagic shock than conventional measurements and thereby better guide initial management. Four groups of five pentobarbital anesthetized Sprague-Dawley rats were randomly assigned to be bled over 30 min in amounts estimated to be 25%, 30%, 35%, or 40% of total blood volume. With an optical PCO2 sensor applied noninvasively to the mucosa of the left inner cheek, PBUCO2 was continuously measured together with arterial pressure, end-tidal PCO2, and intermittent measurement of cardiac output, arterial blood lactate, and base deficit. Surviving animals had free access to water and food but no other treatment during the 72-h interval after recovery from anesthesia. After an estimated 40% blood loss, all animals died within 1 h. In the remaining animals, arterial pressure, end-tidal carbon dioxide, cardiac index, blood lactate, and base deficit each failed to discriminate among animals with 35%, 30%, and 25% acute blood losses. This contrasted with PBUCO2, which discriminated between the magnitude of massive blood loss and untreated survival. Buccal mucosal PCO2 was predictive of outcome after rapid bleeding when compared with arterial pressure, end-tidal carbon dioxide, cardiac index, arterial blood lactate, and base deficit. This measurement is therefore likely to serve as a useful guide for the immediate management of hemorrhagic shock.

Increases in tissue Pco2 during circulatory shock reflect selective decreases in capillary blood flow.

OBJECTIVES: Tissue Pco2 reflects metabolic alterations due to circulatory failure during circulatory shock. This study addresses simultaneous changes in gastric and buccal tissue Pco2 with changes in microcirculatory blood flow in a rat model of circulatory shock induced by cecal ligation and puncture. DESIGN: Prospective controlled laboratory study. SETTING: University-affiliated research laboratory. SUBJECTS: Male breeder Sprague-Dawley rats. INTERVENTIONS: Induction of polymicrobial, abdominal sepsis by cecal ligation and puncture. MEASUREMENTS AND MAIN RESULTS: Tissue Pco2 was continuously measured with the aid of a miniature carbon dioxide electrode. Using orthogonal polarization spectral imaging, recordings of the microcirculation were taken at baseline and hourly intervals until death and compared with sham-operated animals. Gastric and buccal tissue Pco2 values progressively increased in animals after cecal ligation and puncture and terminated in death. Microcirculatory blood flow in vessels >20 microm was well preserved during progression of shock, whereas there was an early and progressive decrease in microcirculatory blood flow in vessels <20 microm, mostly representing capillaries. Tissue Pco2, the tissue Pco2-Paco2 gradient, and blood flow in vessels <20 microm were highly correlated. This contrasted with sham control animals in which no significant hemodynamic, blood gas, lactate, microcirculatory, and tissue Pco2 abnormalities were observed. CONCLUSIONS: These observations suggest that microcirculatory failure in capillaries appears as an early defect in close association with anaerobic metabolism during progression of circulatory shock in an animal model of septic peritonitis.

Levosimendan improves postresuscitation outcomes in a rat model of CPR.

In this study we sought to determine whether a calcium sensitizer, levosimendan, would have a more favorable effect on postresuscitation myocardial function and, consequently, postresuscitation survival than beta-adrenergic dobutamine. The extreme decrease in survival before hospital discharge of resuscitated victims is attributed, in part, to postresuscitation myocardial failure, and dobutamine has been recommended for the management of postresuscitation myocardial failure. We studied a total of 15 animals. Ventricular fibrillation was induced in Sprague-Dawley rats weighing 450 to 550 g. Cardiopulmonary resuscitation (CPR), including chest compressions and mechanical ventilation, was begun after 8 minutes of untreated cardiac arrest. Electrical defibrillation was attempted after 6 minutes of CPR. Each animal was resuscitated. Animals were randomized to undergo treatment with levosimendan, dobutamine, or saline-solution placebo. These agents were administered 10 minutes after the return of spontaneous circulation. Levosimendan was administered in a loading dose of 12 microg kg(-1) over a 10-minute period, followed by infusion of 0.3 microg kg(-1) min(-1) over the next 230 minutes. Dobutamine was continuously infused at a dosage of 3 microg kg(-1) min(-1). Saline-solution placebo was administered in the same volume and over the same amount of time as levosimendan. Levosimendan and dobutamine produced comparable increases in cardiac output and rate of left-ventricular pressure increase. However, administration of levosimendan resulted in lower heart rates and lesser increases in left ventricular diastolic pressure compared with both dobutamine and placebo. The duration of postresuscitation survival was significantly greater with levosimendan (16 +/- 2 hours), intermediate with dobutamine (11 +/- 2 hours) and least with saline-solution placebo (8 +/- 1 hour). Levosimendan and dobutamine both improved postresuscitation myocardial function. However, levosimendan produced more favorable postresuscitation myocardial function and increased the duration of postresuscitation survival.

Nonselective beta-blocking agent improves the outcome of cardiopulmonary resuscitation in a rat model.

OBJECTIVE: Postresuscitation myocardial dysfunction has been recognized as a leading cause of early death after initial successful resuscitation. Recent experimental and clinical studies have indicated that the beta-adrenergic effect of epinephrine significantly increases the severity of postresuscitation myocardial dysfunction. The fact that beta-adrenergic stimulation increases myocardial oxygen consumption during ventricular fibrillation is an important implication with respect to both the exogenous in terms of pharmacologic interventions during cardiopulmonary resuscitation and the endogenous as the result of intense sympathetic activation of cardiovascular collapse. Earlier experimental evidence has indicated that oxygenation improved by beta-blockade and beta1-blocking agent did offset the adverse effect of epinephrine. This prompted us to investigate the effect of beta-blockade on both exogenous and endogenous beta stimulation in an established rat model. DESIGN: Prospective, randomized, controlled study. SETTING: Animal research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: In this series of studies, propranolol was administrated before ventricular fibrillation as a pretreatment combined with epinephrine treatment during precordial compression and then alone in a prolonged cardiac arrest setting. MEASUREMENTS AND MAIN RESULTS: Improved postresuscitation myocardial dysfunction (cardiac index, dP/dt40, -dP/dt) was observed with propranolol, a nonselective beta-adrenergic blocker, in pretreated animals such that the beneficial effects were associated with better postresuscitation survival. CONCLUSION: Nonselective beta-blockade improved the outcome of cardiopulmonary resuscitation in a rat model and deserves further evaluation in settings of cardiopulmonary resuscitation.

Beta1-adrenergic blockade during cardiopulmonary resuscitation improves survival.

OBJECTIVE: The short-acting beta1-selective adrenergic blocking agent, esmolol, was administrated during cardiopulmonary resuscitation with the hypothesis that initial resuscitation and postresuscitation survival would be improved. DESIGN: Prospective, randomized, controlled study. SETTING: Animal research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Ventricular fibrillation was induced in 18 male Sprague-Dawley rats, which were then left untreated for 6 mins before attempted resuscitation with precordial compression, mechanical ventilation, and electrical defibrillation. Animals were randomized to receive 300 microg/kg esmolol in a volume of 200 microL or an equivalent volume of saline placebo during cardiopulmonary resuscitation. Electrical defibrillation was attempted after 12 mins of ventricular fibrillation. MEASUREMENTS AND MAIN RESULTS: Esmolol-treated animals required a significantly smaller number of electrical shocks before resuscitation. Each of the esmolol-treated but only five of nine placebo-treated animals were successfully resuscitated. Postresuscitation contractile and left ventricular diastolic functions of resuscitated animals were significantly better after esmolol administration and duration of survival was significantly increased. CONCLUSIONS: A short-acting beta1-selective adrenergic blocking agent, when administered during cardiopulmonary resuscitation, significantly improved initial cardiac resuscitation, minimized postresuscitation myocardial dysfunction, and increased the duration of postresuscitation survival.