Avoiding, Not Managing, Drug Withdrawal Syndrome in the Setting of COVID-19 Acute Respiratory Distress Syndrome. Comment on Ego et al. How to Manage Withdrawal of Sedation and Analgesia in Mechanically Ventilated COVID-19 Patients? J. Clin. Med. 2021, 10, 4917.

The management of sedation in the setting of COVID-19 ("COVID") by Ego et al. [...].

How should dexmedetomidine and clonidine be prescribed in the critical care setting? / Como a dexmedetomidina e a clonidina devem ser prescritas no ambiente de terapia intensiva?

Cardiac, ventilatory and kidney management in the critical care setting has been optimized over the past decades. Cognition and sedation represent one of the last remaning challenges. As conventional sedation is suboptimal and as the sedation evoked by alpha-2 adrenergic agonists ("cooperative" sedation with dexmedetomidine, clonidine or guanfacine) represents a valuable alternative, this manuscript covers three practical topics for which evidence-based medicine is lacking: a) Switching from conventional to cooperative sedation ("switching"): the short answer is the abrupt withdrawal of conventional sedation, immediate implementation of alpha-2 agonist infusion and the use of "rescue sedation" (midazolam bolus[es]) or "breakthrough sedation" (haloperidol bolus[es]) to stabilize cooperative sedation. b) Switching from conventional to cooperative sedation in unstable patients (e.g., refractory delirium tremens, septic shock, acute respiratory distress syndrome, etc.): to avoid hypotension and bradycardia evoked by sympathetic deactivation, the short answer is to maintain the stroke volume through volume loading, vasopressors and inotropes. c) To avoid these switches and associated difficulties, alpha-2 agonists may be considered first-line sedatives. The short answer is to administer alpha-2 agonists slowly from admission or endotracheal intubation up to stabilized cooperative sedation. The "take home" message is as follows: a) alpha-2 agonists are jointly sympathetic deactivators and sedative agents; b) sympathetic deactivation implies maintaining the stroke volume and iterative assessment of volemia. Evidence-based medicine should document our propositions.

O manejo cardíaco, ventilatório e renal no ambiente de terapia intensiva tem melhorado nas últimas décadas. Cognição e sedação representam dois dos últimos desafios a vencer. Como a sedação convencional não é ideal, e a sedação evocada por agonistas adrenérgicos alfa-2 (sedação "cooperativa" com dexmedetomidina, clonidina ou guanfacina) representa uma alternativa valiosa, este artigo abrange três tópicos práticos para os quais há lacunas na medicina baseada em evidência. O primeiro deles é a mudança de sedação convencional para sedação cooperativa ("mudança"): a resposta curta consiste em retirada abrupta de sedação convencional, implantação imediata de infusão de um agonista alfa-2 e uso de "sedação de resgate" (bolos de midazolam) ou "sedação agressiva" (haloperidol em bolos) para estabilizar a sedação cooperativa. O segundo tópico é a mudança de sedação convencional para sedação cooperativa em pacientes instáveis (por exemplo: delirium tremens refratário, choque séptico, síndrome do desconforto respiratório agudo etc.), pois, para evitar a hipotensão e a bradicardia provocadas por desativadores simpáticos, a resposta curta é manter o volume sistólico por administração de volume, vasopressores e inotrópicos. Por fim, para evitar essas mudanças e dificuldades associadas, os agonistas alfa-2 podem ser sedativos de primeira linha. A resposta curta é administrar agonistas alfa-2 lentamente desde a admissão ou intubação endotraqueal, até estabilização da sedação cooperativa. Dessa forma, conclui-se que os agonistas alfa-2 são, ao mesmo tempo, agentes desativadores simpáticos e sedativos, bem como a desativação simpática implica na manutenção do volume sistólico e na avaliação persistente da volemia. A medicina baseada em evidência deve documentar esta proposta.

Is the Sympathetic System Detrimental in the Setting of Septic Shock, with Antihypertensive Agents as a Counterintuitive Approach? A Clinical Proposition.

Mortality in the setting of septic shock varies between 20% and 100%. Refractory septic shock leads to early circulatory failure and carries the worst prognosis. The pathophysiology is poorly understood despite studies of the microcirculatory defects and the immuno-paralysis. The acute circulatory distress is treated with volume expansion, administration of vasopressors (usually noradrenaline: NA), and inotropes. Ventilation and anti-infectious strategy shall not be discussed here. When circulation is considered, the literature is segregated between interventions directed to the systemic circulation vs. interventions directed to the micro-circulation. Our thesis is that, after stabilization of the acute cardioventilatory distress, the prolonged sympathetic hyperactivity is detrimental in the setting of septic shock. Our hypothesis is that the sympathetic hyperactivity observed in septic shock being normalized towards baseline activity will improve the microcirculation by recoupling the capillaries and the systemic circulation. Therefore, counterintuitively, antihypertensive agents such as beta-blockers or alpha-2 adrenergic agonists (clonidine, dexmedetomidine) are useful. They would reduce the noradrenaline requirements. Adjuncts (vitamins, steroids, NO donors/inhibitors, etc.) proposed to normalize the sepsis-evoked vasodilation are not reviewed. This itemized approach (systemic vs. microcirculation) requires physiological and epidemiological studies to look for reduced mortality.

Como a dexmedetomidina e a clonidina devem ser prescritas no ambiente de terapia intensiva? / How should dexmedetomidine and clonidine be prescribed in the critical care setting?

RESUMO O manejo cardíaco, ventilatório e renal no ambiente de terapia intensiva tem melhorado nas últimas décadas. Cognição e sedação representam dois dos últimos desafios a vencer. Como a sedação convencional não é ideal, e a sedação evocada por agonistas adrenérgicos alfa-2 (sedação "cooperativa" com dexmedetomidina, clonidina ou guanfacina) representa uma alternativa valiosa, este artigo abrange três tópicos práticos para os quais há lacunas na medicina baseada em evidência. O primeiro deles é a mudança de sedação convencional para sedação cooperativa ("mudança"): a resposta curta consiste em retirada abrupta de sedação convencional, implantação imediata de infusão de um agonista alfa-2 e uso de "sedação de resgate" (bolos de midazolam) ou "sedação agressiva" (haloperidol em bolos) para estabilizar a sedação cooperativa. O segundo tópico é a mudança de sedação convencional para sedação cooperativa em pacientes instáveis (por exemplo: delirium tremens refratário, choque séptico, síndrome do desconforto respiratório agudo etc.), pois, para evitar a hipotensão e a bradicardia provocadas por desativadores simpáticos, a resposta curta é manter o volume sistólico por administração de volume, vasopressores e inotrópicos. Por fim, para evitar essas mudanças e dificuldades associadas, os agonistas alfa-2 podem ser sedativos de primeira linha. A resposta curta é administrar agonistas alfa-2 lentamente desde a admissão ou intubação endotraqueal, até estabilização da sedação cooperativa. Dessa forma, conclui-se que os agonistas alfa-2 são, ao mesmo tempo, agentes desativadores simpáticos e sedativos, bem como a desativação simpática implica na manutenção do volume sistólico e na avaliação persistente da volemia. A medicina baseada em evidência deve documentar esta proposta.

ABSTRACT Cardiac, ventilatory and kidney management in the critical care setting has been optimized over the past decades. Cognition and sedation represent one of the last remaning challenges. As conventional sedation is suboptimal and as the sedation evoked by alpha-2 adrenergic agonists ("cooperative" sedation with dexmedetomidine, clonidine or guanfacine) represents a valuable alternative, this manuscript covers three practical topics for which evidence-based medicine is lacking: a) Switching from conventional to cooperative sedation ("switching"): the short answer is the abrupt withdrawal of conventional sedation, immediate implementation of alpha-2 agonist infusion and the use of "rescue sedation" (midazolam bolus[es]) or "breakthrough sedation" (haloperidol bolus[es]) to stabilize cooperative sedation. b) Switching from conventional to cooperative sedation in unstable patients (e.g., refractory delirium tremens, septic shock, acute respiratory distress syndrome, etc.): to avoid hypotension and bradycardia evoked by sympathetic deactivation, the short answer is to maintain the stroke volume through volume loading, vasopressors and inotropes. c) To avoid these switches and associated difficulties, alpha-2 agonists may be considered first-line sedatives. The short answer is to administer alpha-2 agonists slowly from admission or endotracheal intubation up to stabilized cooperative sedation. The "take home" message is as follows: a) alpha-2 agonists are jointly sympathetic deactivators and sedative agents; b) sympathetic deactivation implies maintaining the stroke volume and iterative assessment of volemia. Evidence-based medicine should document our propositions.

Building on the Shoulders of Giants: Is the use of Early Spontaneous Ventilation in the Setting of Severe Diffuse Acute Respiratory Distress Syndrome Actually Heretical?

Acute respiratory distress syndrome (ARDS) is not a failure of the neurological command of the ventilatory muscles or of the ventilatory muscles; it is an oxygenation defect. As positive pressure ventilation impedes the cardiac function, paralysis under general anaesthesia and controlled mandatory ventilation should be restricted to the interval needed to control the acute cardio-ventilatory distress observed upon admission into the critical care unit (CCU; "salvage therapy" during "shock state"). Current management of early severe diffuse ARDS rests on a prolonged interval of controlled mechanical ventilation with low driving pressure, paralysis (48 h, too often overextended), early proning and positive end-expiratory pressure (PEEP). Therefore, the time interval between arrival to the CCU and switching to spontaneous ventilation (SV) is not focused on normalizing the different factors involved in the pathophysiology of ARDS: fever, low cardiac output, systemic acidosis, peripheral shutdown (local acidosis), supine position, hypocapnia (generated by hyperpnea and tachypnea), sympathetic activation, inflammation and agitation. Then, the extended period of controlled mechanical ventilation with paralysis under general anaesthesia leads to CCU-acquired pathology, including low cardiac output, myoneuropathy, emergence delirium and nosocomial infection. The stabilization of the acute cardio-ventilatory distress should primarily itemize the pathophysiological conditions: fever control, improved micro-circulation and normalized local acidosis, 'upright' position, minimized hypercapnia, sympathetic de-activation (normalized sympathetic activity toward baseline levels resulting in improved micro-circulation with alpha-2 agonists administered immediately following optimized circulation and endotracheal intubation), lowered inflammation and 'cooperative' sedation without respiratory depression evoked by alpha-2 agonists. Normalised metabolic, circulatory and ventilatory demands will allow one to single out the oxygenation defect managed with high PEEP (diffuse recruitable ARDS) under early spontaneous ventilation (airway pressure release ventilation+SV or low-pressure support). Assuming an improved overall status, PaO2/FiO2≥150-200 allows for extubation and continuous non-invasive ventilation. Such fast-tracking may avoid most of the CCU-acquired pathologies. Evidence-based demonstration is required.

Early severe acute respiratory distress syndrome: What's going on? Part I: pathophysiology.

Severe acute respiratory distress syndrome (ARDS, PaO2/FiO2 < 100 on PEEP ≥ 5 cm H2O) is treated using controlled mechanical ventilation (CMV), recently combined with muscle relaxation for 48 h and prone positioning. While the amplitude of tidal volume appears set < 6 mL kg⁻¹, the level of positive end-expiratory pressure (PEEP) remains controversial. This overview summarizes several salient points, namely: a) ARDS is an oxygenation defect: consolidation/ difuse alveolar damage is reversed by PEEP and/or prone positioning, at least during the early phase of ARDS b) ARDS is a dynamic disease and partially iatrogenic. This implies that the management of the ventilator may be a life-saver by reducing the duration of mechanical ventilation, or detrimental by extending this duration, leading into critical care-acquired diseases. Indeed, a high PEEP (10-24 cm H2O) appears to be a life-saver in the context of early severe diffuse ARDS; c) tidal volume and plateau pressure cannot be identical for all patients; d) the only remaining rationale for CMV and muscle relaxation is to suppress patient-ventilator asynchrony and to lower VO2, during the acute cardio-ventilatory distress. Therefore, in early severe diffuse ARDS, this review argues for a combination of a high PEEP (preferably titrated on transpulmonary pressure) with spontaneous ventilation + pressure support (or newer modes of ventilation). However, conditionalities are stringent: upfront circulatory optimization, upright positioning, lowered VO2, lowered acidotic and hypercapnic drives, sedation without ventilatory depression and without lowered muscular tone. As these propositions require evidence-based demonstration, the accepted practice remains, in 2016, controlled mechanical ventilation, muscle relaxation, and prone position.

Early severe acute respiratory distress syndrome: What's going on? Part II: controlled vs. spontaneous ventilation?

The second part of this overview on early severe ARDS delineates the pros and cons of the following: a) controlled mechanical ventilation (CMV: lowered oxygen consumption and perfect patient-to-ventilator synchrony), to be used during acute cardio-ventilatory distress in order to "buy time" and correct circulatory insufficiency and metabolic defects (acidosis, etc.); b) spontaneous ventilation (SV: improved venous return, lowered intrathoracic pressure, absence of muscle atrophy). Given a stabilized early severe ARDS, as soon as the overall clinical situation improves, spontaneous ventilation will be used with the following stringent conditionalities: upfront circulatory optimization, upright positioning, lowered VO2, lowered acidotic and hypercapnic drives, sedation without ventilatory depression and without lowered muscular tone, as well as high PEEP (titrated on transpulmonary pressure, or as a second best: "trial"-PEEP) with spontaneous ventilation + pressure support (or newer modes of ventilation). As these propositions require evidence-based demonstration, the reader is reminded that the accepted practice remains, in 2016, controlled mechanical ventilation, muscle relaxation and prone position.

Swift recovery of severe acute hypoxemic respiratory failure under non-invasive ventilation.

BACKGROUND: In the setting of severe acute respiratory distress syndrome (ARDS; PaO2/FiO2 < 100), the cut-off point for switching from non-invasive ventilation to intubation combined to mechanical ventilation is poorly defined. RESULTS: The swift resolution over 10 h of a severe acute hypoxemic respiratory failure (P/F = 57) caused by aspiration following heroin overdose, using non-invasive ventilation (NIV)-high PEEP (15-20 cm H2O)-low pressure support (8 cm H20) is reported. The success in treating non-invasively severe hypoxia was presumably linked to a highly restricted subset: healthy young patient, minimal alteration of consciousness, non-combativeness, absence of severe metabolic acidosis, quick resolution of supraventricular arrhythmia, one-to-one supervision by the intensivist in the critical care unit. CONCLUSION: Given the complications associated with tracheal intubation and mechanical ventilation on the one hand and with delayed intubation on the other hand, high PEEP-NIV may warrant study in a restricted set of patients closely monitored in a critical care environment.

Hemostasis dynamics during coagulopathy resulting from Echis envenomation.

This work provides a graphic description of the time course of hemostasis tests results during spontaneous evolution of Echis envenoming and correction of hemostasis disorders with antivenom therapy. The dynamics of fibrinogenemia (g L(-1)), prothrombin time (PT, %), activated partial thromboplastin time (aPTT, patient/normal ratio) and platelet count (Giga L(-1)) were collected from coagulopathic envenomed patients of a 12 years prospective study in Africa. Sixty patients were included. 47 of them (78%) received an antivenom (33 ± 12 ml) and 13 did not. Thirty patients (50%) presented bleeding. Only one patient died. The time for fibrinogen to be more than 1 g L(-1) was 181 ± 116 h (7.5 days) in the spontaneous evolution group versus 40 ± 21 h in the antivenom group (p < 0.0001). The times for reaching a PT above 50% were 140 ± 64 min (5.8 days) versus 25 ± 15 h (p < 0.00001) and for reaching an aPTT less than 1.5 times the normal values, 116 ± 76 h (4.7 days) versus 10 ± 9 h respectively (p < 0.0002). Thrombopenia was not a common feature of Echis envenomation. This study is the first one to provide a chart of the evolution of the hemostatic tests during envenomation caused by Echis bites. The plots enable to estimate that, in Echis envenomation, in the absence of antivenom administration, hemostasis remains severely affected until the 8-10th day of evolution. On the contrary, efficient antivenom against African vipers corrects clotting functions within a few hours.

Antivenin remains effective against African Viperidae bites despite a delayed treatment.

BACKGROUND: Viperidae bites represent a public health issue in Africa and are responsible for a hemorrhagic syndrome with fatal outcome in the short term. A research on Medline database does not reveal any data definitively demonstrating the efficiency of antivenom in case of delayed administration. The aim of this study, based on a 12-year survey of viperine syndromes in Republic of Djibouti, was to compare the normalization of the hemostasis disorders with an early administration of antivenin versus a delayed administration. METHODS: A retrospective study was conducted from October 1994 to May 2006 in the intensive care unit of the French military Hospital, in Djibouti. Seventy-three Viperidae-envenomed patients were included. Antivenin efficiency in correcting hemostatic disorders was analyzed in relation to time to treatment (before or after the 24th hour after the bite). RESULTS: Forty-two patients (58%) presented with bleeding. A consumptive coagulopathy was found in 68 patients (93%). Antivenin was observed to be effective in improving hemostasis, and the time to normalization of biologic parameters was similar, whether the treatment was started before or after the 24th hour after the bite. CONCLUSION: Antivenin should ideally be administered as early as possible. However, in Africa, time to treatment generally exceeds 24 hours. The results of the present evidence-based study confirm an empirical concept: a delayed time to treatment should in no way counterindicate the use of antivenin immunotherapy, in the case of African Viperidae bites.

Clinical and therapeutic aspects of childhood kerosene poisoning in Djibouti.

We report a prospective and descriptive study about childhood acute poisoning with kerosene in Djibouti. Acute poisoning is a common and stable occurrence in low socioeconomic groups in Africa, where negligence is the main cause of poisoning. The respiratory system was the main target, with 41% of patients having pneumonia, which may become life-threatening, but with low mortality rate. Asymptomatic patients (35%) can be discharged, while those with pulmonary or neurological signs must be admitted for observation and supportive treatment based on oxygen administration. Our study suggests management and provides a discussion for therapeutic options and emphasizes the importance of prevention.

The use of boluses of propofol for the management of severe tetanus in a child.

Tetanus is endemic in many developing countries. Although propofol has been proposed for sedation in tetanus, the routine use of this drug has not been clearly documented in published reports. A few studies have reported its beneficial effects but no randomized studies are available. We describe the case of a five-year-old boy who presented with severe tetanus in East Africa. The antispastic therapy consisted of benzodiazepine infusion with the addition of titrated boluses of propofol. Intubation and mechanical ventilation were avoided.

Laryngeal dyspnea in relation to an interaction between acenocoumarol and topical econazole lotion.

BACKGROUND: Bleeding is the most serious complication of oral anticoagulant therapy used for the prevention of thromboembolic complications. Drug-drug interactions are an important concern, as they may increase drug toxicity and, in the case of anticoagulant therapies, increase the risk of hemorrhage. CASE SUMMARY: An 84-year-old woman presented to the emergency department with a bilateral cervical hematoma and symptoms of upper-airway obstruction that had been increasing for 72 hours, with dyspnea and difficulty speaking developing in the previous 24 hours. Transnasal fiberoptic laryngoscopy revealed a significant laryngeal hematoma, as well as a hematoma on the floor of the mouth and in the tonsil area. Laboratory abnormalities included a prothrombin time < 10%, an international normalized ratio exceeding the laboratory limits, and an activated partial thromboplastin time >120 seconds. The patient had been receiving acenocoumarol 4 mg/d for 10 years for episodes of atrial fibrillation and recurrent deep venous thrombosis. Seventeen days earlier, she had received a prescription for topical econazole lotion 1% to be applied 3 times daily for 1 month to treat a dermatitis affecting 12% of the body surface. The patient was admitted to the intensive care unit for treatment of respiratory failure, where oxygen was delivered by face mask. The coagulation disorders were treated with prothrombin complex concentrate 30 IU/kg IV and vitamin K1 10 mg IV, and values normalized within 36 hours. Surgical evacuation of the laryngeal hematoma was not necessary. After 48 hours, improvement in the patient's respiratory symptoms allowed transfer to the ear, nose, and throat unit, where daily endoscopic examination was performed. Aspirin was substituted for acenocoumarol, and the patient returned home after 10 days without sequelae. Based on a Naranjo score of 7, this episode was probably related to an interaction between acenocoumarol and econazole. CONCLUSION: This report describes a case of a probable interaction between topical econazole lotion 1% and acenocoumarol that resulted in overanticoagulation and a life-threatening laryngeal hematoma in this elderly patient.