Pathophysiology of Respiratory Failure Following Acute Organophosphate Poisoning : A Dissertation

Organophosphate (OP) poisoning is a health issue worldwide with over 200,000 deaths per year. Although not a problem in most developed countries, in some third world countries, one third of a hospital’s population could be patients with OP exposure. Even with the most aggressive therapy, 10-40% of patients admitted to an intensive care unit will die. Research into the best practice for treating OP poisoning is lacking, due somewhat to a lack of detailed understanding of the physiology of OP poisoning. Our research uses animal models of acute OP poisoning to explore the mechanism of OP-induced respiratory failure. Our research shows that animals poisoned with dichlorvos demonstrated a uniformly fatal central apnea that, if prevented, was followed immediately by a variable pulmonary dysfunction. Potential mechanisms for dichlorvos-induced central apnea can be divided into direct effects on the central respiratory oscillator (CRO) and feedback inhibition of the CRO. Two afferent pathways that can induce apnea include vagal feedback pathways and feed-forward pathways from the cerebral hemispheres. In our studies we found that vagal feedback and feed forward inhibition from the cerebral hemispheres were not required for OP-induced central apnea. The pre-Botzinger complex in the brainstem is thought to be the kernel of the CRO, but exposure of the pre-Botzinger complex to dichlorvos was not sufficient for apnea. Although OP induced central apnea was uniformly fatal, partial recovery of the CRO occurred post apnea with mechanical ventilation. Central apnea was ubiquitous in our rat poisoning model, but pulmonary dysfunction was extremely variable, with a range of pulmonary effects from fulminate pulmonary failure with prominent pulmonary secretions to no pulmonary dysfunction at all. Vagal efferent activity is involved in neural control of pulmonary tissue but the vagus was not involved in OP-induced pulmonary dysfunction. Anti-muscarinic medications are the mainstay of clinical therapy and are commonly dosed by their effects on pulmonary secretions. Our studies found that atropine (the most common therapeutic agent for OP poisoning) resulted in a ventilation-perfusion mismatch secondary to effects on the pulmonary vasculature

Development and validation of a novel image quality rating scale for echocardiography during cardiac arrest

Objective: Research into echocardiography (echo) during cardiac arrest has suffered from methodological flaws that limit aggregation of findings. We developed and validated a novel image rating scale for qualitative analysis of echo images obtained during resuscitation. Methods: A novel 5-point ordinal rating scale was developed and validated using recorded echo images from 145 consecutive cardiac arrest patients. Recorded echo images were reviewed in a blinded fashion by investigators experienced in cardiac arrest echo, and image quality was rated using this scale. Cardiac activity was subsequently classified as no activity, disorganized activity and organized activity. The primary outcome was inter-rater agreement using the image quality rating scale. Secondary outcome was the qualitative evaluation of the type of cardiac activity. Results: A total of 235 ultrasounds were analyzed by study investigators using the image quality rating scale. The overall image quality agreement between reviewers using the scale was good with a weighted kappa of 0.65. Agreement for image quality in subxyphoid images was greater than in parasternal images (0.65-0.52). Echo analysis of cardiac activity showed no activity (33%), disorganized activity (18%), and organized activity (49%). Agreement was great for presence or absence of cardiac activity and organized cardiac activity with a kappa of 0.84 and 0.78. Conclusions: A novel image quality rating scale for echo during cardiac arrest demonstrates substantial agreement between reviewers. Agreement regarding the presence or absence, as well as the organization of cardiac activity was substantial

Inferior vena cava displacement during respirophasic ultrasound imaging

BACKGROUND: Ultrasound measurement of dynamic changes in inferior vena cava (IVC) diameter can be used to assess intravascular volume status in critically ill patients, but published studies vary in accuracy as well as recommended diagnostic cutoffs. Part of this variability may be related to movements of the vessel relative to the transducer during the respiratory cycle which results in unintended comparison of different points of the IVC at end expiration and inspiration, possibly introducing error related to variations in normal anatomy. The objective of this study was to quantify both craniocaudal and mediolateral movements of the IVC as well as the vessel\u27s axis of collapse during respirophasic ultrasound imaging. METHODS: Patients were enrolled from a single urban academic emergency department with ultrasound examinations performed by sonographers experienced in IVC ultrasound. The IVC was imaged from the level of the diaphragm along its entire course to its bifurcation with diameter measurements and respiratory collapse measured at a single point inferior to the confluence of the hepatic veins. While imaging the vessel in its long axis, movement in a craniocaudal direction during respiration was measured by tracking the movement of a fixed point across the field of view. Likewise, imaging the short axis of the IVC allowed for measurement of mediolateral displacement as well as the vessel\u27s angle of collapse relative to vertical. RESULTS: Seventy patients were enrolled over a 6-month period. The average diameter of the IVC was 13.8 mm (95% CI 8.41 to 19.2 mm), with a mean respiratory collapse of 34.8% (95% CI 19.5% to 50.2%). Movement of the vessel relative to the transducer occurred in both mediolateral and craniocaudal directions. Movement was greater in the craniocaudal direction at 21.7 mm compared to the mediolateral movement at 3.9 mm (p \u3c 0.001). Angle of collapse assessed in the transverse plane averaged 115 degrees (95% CI 112 degrees to 118 degrees ). CONCLUSIONS: Movement of the IVC occurs in both mediolateral and craniocaudal directions during respirophasic ultrasound imaging. Further, collapse of the vessel occurs not at true vertical (90 degrees ) but 25 degrees off this axis. Technical approach to IVC assessment needs to be tailored to account for these factors

Ultrasound in Emergency Medicine LEARNING CURVE OF BEDSIDE ULTRASOUND OF THE GALLBLADDER

e Abstract-Existing guidelines for the number of ultrasounds required before clinical competency are based not on scientific study but on consensus opinion. The objective of this study was to describe the learning curve of limited right upper quadrant ultrasound. This was a prospective descriptive study. Ultrasounds collected over 1 year were reviewed for interpretive and technical errors. Possible errors during bedside ultrasound of the gallbladder include incorrect interpretation, incomplete image acquisition, and improper or poor imaging techniques resulting in poor image quality. The ultrasound image quality was rated on a 4-point scale, with 1 ‫؍‬ barely interpretable and 4 ‫؍‬ excellent image quality. Required images were rated on an additional 4-point scale, with 4 ‫؍‬ all required images were included and 1 ‫؍‬ minimal images were recorded. There were 352 patients enrolled by 42 emergency physicians (35 residents and 7 attendings). Gallstones were identified in 13.9% of the patients, and 4.3% of the ultrasounds were indeterminate. Interpretive and technical error rates decreased as the clinician gained experience. The number of poor quality ultrasounds decreased after an average of seven ultrasounds. Inclusion of all required images increased after 25 ultrasounds. Sonographers who had performed over 25 ultrasounds showed excellent agreement with the expert over-read, with only two disagreements, both from a single individual. It was concluded that clinicians are clinically competent after performing 25 ultrasounds of the gallbladder

Echocardiographic pre-pause imaging and identifying the acoustic window during CPR reduces CPR pause time during ACLS - A prospective Cohort Study

Objectives: Pre-pause imaging during cardiopulmonary resuscitation (CPR) involves the acquisition of poor-quality, brief images immediately prior to stopping CPR to allow shorter, better-quality images during the pause. We hypothesize that pre-pause imaging is associated with a decrease in CPR pause length and shorter image acquisition time. Methods: Prospective, interventional cohort study enrolling out-of-hospital (OOH) cardiac arrest patients. Pre-pause imaging involves pre-localizing of the approximate sonographic window during CPR to support subsequent fine tuning when CPR pauses. Physicians were educated on pre-pause imaging and data was recorded prior- and post- introduction of pre-pause imaging into American cardiac life support (ACLS). Timing of CPR pauses and identification of interventions and events during pause were recorded (e.g., intubation, defibrillation, multiple cardiac ultrasounds). Ultrasound (US) images were reviewed for image quality using a 5-point scale. Primary outcome was length of CPR pause with and without pre-pause imaging. Secondary outcome included US length. Results: One hundred and forty five subjects presenting after OOH cardiac arrest were enrolled over 13 months, 70 during the baseline period prior to pre-pause imaging and 75 after pre-pause imaging was integrated into ACLS. Pre-pause imaging decreased CPR pause length from 28.3 s (95%CI 25.1-31.5) to 12.8 s (95%CI 11.9-13.7). US image acquisition time decreased with pre-pause imaging from 20.4 (95%CI 18.0-22.7) to 11.0 s (95%CI 10.1-11.8). US image quality was unchanged despite the decrease in image acquisition time. (3.0 (95%CI 2.8-3.2) vs 2.7 (95%CI 2.5-2.9)). Multivariate modeling showed that ultrasound did not prolong CPR pause length. Conclusion: Pre-pause imaging was associated with significant decrease in CPR pause length and US image acquisition time. Pre-pause imaging should be encouraged for any clinicians who use ultrasound during ACLS

Pathophysiology of respiratory failure following acute dichlorvos poisoning in a rodent model

Organophosphate (OP) poisoning causes a cholinergic crisis with a wide range of clinical effects including central apnea, pulmonary bronchoconstriction and secretions, seizures, and muscle weakness. The morbidity and mortality from acute OP poisoning is attributed to respiratory failure but the relative contributions of the central and peripheral effects in producing collapse of the respiratory system are unclear. In this study we used a novel adult rat model of acute OP poisoning to analyze the pathophysiology of acute OP poisoning. We found that poisoning caused rapidly lethal central apnea. In animals sustained with mechanical ventilation, we found that following central apnea there ensued progressive pulmonary insufficiency that was variable in timing and severity. Our findings support the hypothesis that OP poisoning in this animal model causes a sequential two hit insult, with rapid central apnea followed by delayed impairment of pulmonary gas exchange with prominent airway secretions

Ultrasound-Guided Drainage for Pediatric Soft Tissue Abscesses Decreases Clinical Failure Rates Compared to Drainage Without Ultrasound: A Retrospective Study

OBJECTIVES: Soft tissue abscesses are common in the pediatric emergency department (ED). Ultrasound (US) can be used to both diagnose soft tissue abscesses as well as guide drainage. We hypothesized that clinical failure rates would be less in pediatric patients with suspected skin abscesses when evaluated with US. METHODS: We performed a retrospective review of suspected pediatric skin abscesses at 4 EDs over a 22-month period. Cases were identified through electronic medical record descriptions, discharge diagnoses, and US database records. Data on US use, findings, and outcomes were abstracted to an electronic database. Comparisons between groups included US versus non-US (primary outcome) as well as surgical drainage vs nonsurgical drainage (secondary outcome). RESULTS: A total of 377 patients were seen with concern for a potential skin abscess; 141 patients (37.4%) underwent US imaging during their visit, and 239 (63.4%) underwent incision and drainage (IandD) during their ED stay: 90 with US and 149 without. The failure rate for patients evaluated with US was significantly lower than that for those evaluated without US (4.4% versus 15.6%; P \u3c .005). Thirty-four (11.3%) of the 302 patients with a diagnosis of an abscess failed therapy: 19 (8.2%) after IandD and 15 (21.1%) after nonsurgical management. Failure after IandD was associated with a smaller abscess cavity on US imaging (17.2 versus 44.8 mm3 ; P \u3c .05). CONCLUSIONS: The use of US for patients with a suspected skin abscess was associated with a reduction in the amount of clinical failure rates after both surgical drainage and nonsurgical therapy. Ultrasound should be used when evaluating or treating patients with abscesses

Dichlorvos exposure to the Kolliker-fuse nuclei is sufficient but not necessary for OP induced apnea

Patients exposed to organophosphate (OP) compounds demonstrate a central apnea. The Kolliker-fuse nuclei (KF) are cholinergic nuclei in the brainstem involved in central respiratory control. We hypothesize that exposure of the KF is both necessary and sufficient for OP induced central apnea. We performed an animal study of acute OP exposure. Anesthetized and spontaneously breathing Wistar rats (n=24) were exposed to a lethal dose of dichlorvos using three experimental models. Experiment 1 (n=8) involved systemic OP poisoning using subcutaneous (SQ) 2,2-dichlorovinyl dimethyl phosphate (dichlorvos) at 100mg/kg or 3x LD50. Experiment 2 (n=8) involved isolated poisoning of the KF using stereotactic microinjections of dichlorvos (625mug in 50mul) into the KF. Experiment 3 (n=8) involved systemic OP poisoning with isolated protection of the KF using SQ dichlorvos (100mg/kg) and stereotactic microinjections of organophosphatase A (OpdA), an enzyme that degrades dichlorvos. Respiratory and cardiovascular parameters were recorded continuously. Animals were followed post exposure for 1h or until death. There was no difference in respiratory depression between animals with SQ dichlorvos and those with dichlorvos microinjected into the KF. Despite differences in amount of dichlorvos (100mg/kg vs. 1.8mg/kg) and method of exposure (SQ vs. CNS microinjection), 10min following dichlorvos both groups (SQ vs. microinjection respectively) demonstrated a similar percent decrease in respiratory rate (51.5 vs. 72.2), minute ventilation (49.2 vs. 68.8) and volume of expired gas (17.5 vs. 0.0). Animals with OpdA exposure to the KF during systemic OP exposure demonstrated less respiratory depression, compared to SQ dichlorvos alone (p \u3c 0.04). No animals with SQ dichlorvos survived past 25min post exposure, compared to 50% of animals with OpdA exposure to the KF. In conclusion, exposure of the KF is sufficient but not necessary for OP induced apnea. Protection of the KF during systemic OP exposure mitigates OP induced apnea

Comparison of outcomes between pulseless electrical activity by electrocardiography and pulseless myocardial activity by echocardiography in out-of-hospital cardiac arrest; secondary analysis from a large, prospective study

OBJECTIVE: To measure prevalence of discordance between electrical activity recorded by electrocardiography (ECG) and myocardial activity visualized by echocardiography (echo) in patients presenting after cardiac arrest and to compare survival outcomes in cohorts defined by ECG and echo. METHODS: This is a secondary analysis of a previously published prospective study at twenty hospitals. Patients presenting after out-of-hospital arrest were included. The cardiac electrical activity was defined by ECG and contemporaneous myocardial activity was defined by bedside echo. Myocardial activity by echo was classified as myocardial asystole--the absence of myocardial movement, pulseless myocardial activity (PMA)--visible myocardial movement but no pulse, and myocardial fibrillation--visualized fibrillation. Primary outcome was the prevalence of discordance between electrical activity and myocardial activity. RESULTS: 793 patients and 1943 pauses in CPR were included. 28.6% of CPR pauses demonstrated a difference in electrical activity (ECG) and myocardial activity (echo), 5.0% with asystole (ECG) and PMA (echo), and 22.1% with PEA (ECG) and myocardial asystole (echo). Twenty-five percent of the 32 pauses in CPR with a shockable rhythm by echo demonstrated a non-shockable rhythm by ECG and were not defibrillated. Survival for patients with PMA (echo) was 29.1% (95%CI-23.9-34.9) compared to those with PEA (ECG) (21.4%, 95%CI-17.7-25.6). CONCLUSION: Patients in cardiac arrest commonly demonstrate different electrical (ECG) and myocardial activity (echo). Further research is needed to better define cardiac activity during cardiac arrest and to explore outcome between groups defined by electrical and myocardial activity

Central respiratory failure during acute organophosphate poisoning

Organophosphate (OP) pesticide poisoning is a global health problem with over 250,000 deaths per year. OPs affect neuronal signaling through acetylcholine (Ach) neurotransmission via inhibition of acetylcholinesterase (AChE), leading to accumulation of Ach at the synaptic cleft and excessive stimulation at post-synaptic receptors. Mortality due to OP agents is attributed to respiratory dysfunction, including central apnea. Cholinergic circuits are integral to many aspects of the central control of respiration, however it is unclear which mechanisms predominate during acute OP intoxication. A more complete understanding of the cholinergic aspects of both respiratory control as well as neural modification of pulmonary function is needed to better understand OP-induced respiratory dysfunction. In this article, we review the physiologic mechanisms of acute OP exposure in the context of the known cholinergic contributions to the central control of respiration. We also discuss the potential central cholinergic contributions to the known peripheral physiologic effects of OP intoxication