Etiologic Workup in Cases of Cryptogenic Stroke: A Systematic Review of International Clinical Practice Guidelines.

Background and Purpose- Identifying the etiology of acute ischemic stroke is essential for effective secondary prevention. However, in at least one third of ischemic strokes, existing investigative protocols fail to determine the underlying cause. Establishing etiology is complicated by variation in clinical practice, often reflecting preferences of treating clinicians and variable availability of investigative techniques. In this review, we systematically assess the extent to which there exists consensus, disagreement, and gaps in clinical practice recommendations on etiologic workup in acute ischemic stroke. Methods- We identified clinical practice guidelines/consensus statements through searches of 4 electronic databases and hand-searching of websites/reference lists. Two reviewers independently assessed reports for eligibility. We extracted data on report characteristics and recommendations relating to etiologic workup in acute ischemic stroke and in cases of cryptogenic stroke. Quality was assessed using the AGREE II tool (Appraisal of Guidelines for Research & Evaluation). Recommendations were synthesized according to a published algorithm for diagnostic evaluation in cryptogenic stroke. Results- We retrieved 16 clinical practice guidelines and 7 consensus statements addressing acute stroke management (n=12), atrial fibrillation (n=5), imaging (n=5), and secondary prevention (n=1). Five reports were of overall high quality. For all patients, guidelines recommended routine brain imaging, noninvasive vascular imaging, a 12-lead ECG, and routine blood tests/laboratory investigations. Additionally, ECG monitoring (>24 hours) was recommended for patients with suspected embolic stroke and echocardiography for patients with suspected cardiac source. Three reports recommended investigations for rarer causes of stroke. None of the reports provided guidance on the extent of investigation needed before classifying a stroke as cryptogenic. Conclusions- While consensus exists surrounding standard etiologic workup, there is little agreement on more advanced investigations for rarer causes of acute ischemic stroke. This gap in guidance, and in the underpinning evidence, demonstrates missed opportunities to better understand and protect against ongoing stroke risk. Registration- URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019127822.

Etiologic workup in cases of cryptogenic stroke: protocol for a systematic review and comparison of international clinical practice guidelines.

BACKGROUND: Stroke is a leading cause of death and disability worldwide. Identifying the aetiology of ischaemic stroke is essential in order to initiate appropriate and timely secondary prevention measures to reduce the risk of recurrence. For the majority of ischaemic strokes, the aetiology can be readily identified, but in at least 30% of cases, the exact aetiology cannot be determined using existing investigative protocols. Such strokes are classed as 'cryptogenic' or as a stroke of unknown origin. However, there exists substantial variation in clinical practice when investigating cases of seemingly cryptogenic stroke, often reflecting local service availability and the preferences of treating clinicians. This variation in practice is compounded by the lack of international consensus as to the optimum level and timing of investigations required following a stroke. To address this gap, we aim to systematically review and compare recommendations in evidence-based clinical practice guidelines (CPGs) that relate to the assessment and investigation of the aetiology of ischaemic stroke, and any subsequent diagnosis of cryptogenic stroke. METHOD: We will search for CPGs using electronic databases (MEDLINE, Health Management Information Consortium (HMIC), EMBASE, and CINAHL), relevant websites and search engines (e.g. guideline specific websites, governmental, charitable, and professional practice organisations) and hand-searching of bibliographies and reference lists. Two reviewers will independently screen titles, abstracts and CPGs using a pre-defined relevance criteria form. From each included CPG, we will extract definitions and terms for cryptogenic stroke; recommendations related to assessment and investigation of the aetiology of stroke, including the grade of recommendations and underpinning evidence. The quality of the included CPGs will be assessed using the AGREE II (Appraisal of Guidelines for Research and Evaluation) tool. Recommendations across the CPGs will be summarised descriptively highlighting areas of convergence and divergence between CPGs. DISCUSSION: To our knowledge, this will be the first review to systematically compare recommendations of international CPGs on investigating the aetiology of ischaemic stroke. The findings will allow for a better understanding of international perspectives on the optimum level of investigations required following a stroke and thus contribute to achieving greater international consensus on best practice in this important and complex area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019127822.

Vagus nerve stimulation decreases left ventricular contractility in vivo in the human and pig heart.

1. Studies of the effect of vagus nerve stimulation on ventricular myocardial function in mammals are limited, particularly in the human. 2. The present study was designed to determine the effect of direct electrical stimulation of the left vagus nerve on left ventricular contractile state in hearts paced at 10 % above the natural rate, in anaesthetised pigs and anaesthetised human subjects undergoing open chest surgery for coronary artery bypass grafting. 3. Contractility of the left ventricle was determined from a series of pressure-volume loops obtained from a combined pressure and conductance (volume) catheter placed in the left ventricle. From the measurements a regression slope of the end-systolic pressure-volume relationship was determined to give end-systolic elastance (Ees), a load-independent measure of contractility. 4. In six anaesthetised open chest pigs, stimulation of the peripheral cut end of the left cervical vagus nerve induced a significant decrease in Ees of 26 +/- 14 %. 5. In nine patients electrical stimulation of the left thoracic vagus nerve close to its cardiac branch resulted in a significant drop in Ees of 38 +/- 16 %. 6. The effects of vagal stimulation were blocked by the muscarinic antagonist glycopyrronium (5 mg kg(-1)). 7. Administration of the beta-adrenoreceptor antagonist esmolol (1 mg kg(-1)) also attenuated the effect of vagal stimulation, indicating a degree of interaction of vagal and sympathetic influences on contractility. 8. These studies show that in the human and pig heart the left vagus nerve can profoundly decrease the inotropic state of the left ventricular myocardium independent of its bradycardic effect.

A novel and simple technique to allow detection of the position of the R-waves from intraventricular pressure waveforms: application to the conductance catheter method.

A simple and novel technique that utilizes the zero-crossing points of the first time derivative of intra-ventricular pressure (dP/dt) to mark systole, is proposed. Discrete differentiation of the sampled pressure waveform is calculated using a difference equation. Filtration of high-frequency noise in dP/dt is achieved using a low-pass Butterworth filter of order 4 and a cutoff frequency of 10 Hz. The filter is realized digitally using infinite impulse response filter stages. Double filtering of discrete dP/dt is used to eliminate time shifts. The methods are evaluated on data obtained from six large, white, anaesthetised and open chest pigs, instrumented with a conductance catheter. The zero-crossing points of the filtered dP/dt compare very well with the R-waves of the electrocardiogram (ECG) as markers of systole. The mean error is 1.3% of the duration of the heartcycle. Significantly, our results provide a solution to a problem often encountered with multiuse pressure-volume catheters when an ECG signal cannot be obtained. In this situation, the zero-crossing points of dP/dt, rather than the R-waves of the ECG, can be used as a marker of systole, thus enabling the construction of end-systolic pressure-volume relations to assess cardiac contractility.

Validation of the conductance catheter method for measurement of ventricular volumes under varying conditions relevant to cardiac surgery.

The development of the conductance catheter method has enabled continuous measurement of intraventricular volume in vivo, thus making assessment of pump performance of the heart in vivo possible using pressure-volume analysis. However, this method has not been validated under conditions where pump rate, conductance, viscosity, and temperature of the fluid in the heart chamber is changed as happens in cardiac surgery. To validate the method, pressure-volume data were measured by conductance catheter in a physical model of the human left ventricle. The volume, salinity, viscosity, and temperature of the fluid inside the model were rigorously controlled. The measured pressure-volume data were compared with the actual values to assess the accuracy and dependence of the conductance-measured volumes on salinity, viscosity, temperature, and pump rate. Conductance-measured volumes were not significantly different over a range of heart rates extending from 60 to 100 beats/min, and they were not significantly different over a salinity range of 0.2 to 2 normal saline, a viscosity range of 2.7 to 3.5 centipoise, or over a temperature range of 20 degrees C to 39 degrees C. The percentage errors between actual stroke volumes and conductance-derived volumes were of the order of 10% on average. Our data shows that for a broad range of conditions normally encountered during cardiac surgery, there is no dependence of conductance-measured volume on heart rate, viscosity, temperature, or salinity, provided the correct value of fluid resistivity is used.

Isometric contraction of arm flexor muscles as a method of evaluating cardiac vagal tone in man.

1. We have previously shown that brief voluntary isometric contractions of upper arm flexor muscles performed for one respiratory cycle elicit a significant decrease in the R-R interval. The present study was designed to determine if similar changes are produced by non-voluntary electrically evoked contractions and, if so, to establish the consistency and repeatability of the associated changes in the R-R interval. 2. The heart rate (R-R interval) response to voluntary or non-voluntary brief isometric contraction equivalent to 40% of the maximum voluntary contraction was studied in 10 healthy young male subjects during controlled ventilation at supine rest. 3. The absolute values of R-R intervals occurring in any one of 10 arbitrary phases of a respiratory cycle were measured and plotted by a computer. 4. Both voluntary and non-voluntary contractions elicited similar changes in heart rate and R-R interval, which were greater during expiration than during inspiration. 5. This confirms our previous finding that the magnitude of the R-R interval changes, with brief isometric contraction, is positively related to the degree of cardiac vagal tone. 6. Analysis of the variability between repeated tests initiated in either inspiration or expiration revealed that there was significantly less variability with the electrically induced contraction. 7. It was concluded that electrically induced contractions of 40% maximal voluntary contraction are a viable alternative to voluntary contractions and provide a more controllable means of measuring cardiac vagal withdrawal.

A controlled comparison of the antihypertensive effects of labetalol and alpha-methyldopa.

An open crossover study was carried out in 10 Arab patients with mild to moderate hypertension to compare the effectiveness and tolerability of labetalol with alpha-methyldopa. Patients were started on either 100 mg labetalol or 250 mg alpha-methyldopa 3-times daily and, if necessary, the dosage adjusted by standard increments every 2 weeks over a period of a month until satisfactory control was achieved. This dosage was then maintained for a further 6 weeks before the patients were crossed over to the alternative treatment, similarly adjusted, after a wash-out period of 2 weeks on placebo. The results showed that both treatments produced effective blood pressure control and there was no significant difference in the maximum reduction achieved. The effect of the two drugs on heart rate was also similar. Both treatments were generally well-tolerated and side-effects were mild and similar with either drug.

Clinical observations on treatment of alkylmercury poisoning in hospital patients.

Twenty-six patients suffering from methylmercury poisoning were treated by different therapeutic regimes. Seven received penicillamine or N-acetyl-d-L-penicillamine, 10 were treated with dimercaprol sulfonate and 9, who could not be treated, were given a placebo and were used as controls. Penicillamine, N-acetyl-d-L-penicillamine, and dimercaprol sulfonate reduced the blood level of mercury and increased its urinary excretion. No appreciable clinical improvement was noticed among the severe or very severe cases, while mild or moderate cases improved clinically irrespective of the treatment given.