Photoplethysmography (PPG) is a simple and low-cost optical technique that can be used to detect blood volume changes in the microvascular bed of tissue. It is often used non-invasively to make measurements at the skin surface. The PPG waveform comprises a pulsatile ('AC') physiological waveform attributed to cardiac synchronous changes in the blood volume with each heart beat, and is superimposed on a slowly varying ('DC') baseline with various lower frequency components attributed to respiration, sympathetic nervous system activity and thermoregulation. Although the origins of the components of the PPG signal are not fully understood, it is generally accepted that they can provide valuable information about the cardiovascular system. There has been a resurgence of interest in the technique in recent years, driven by the demand for low cost, simple and portable technology for the primary care and community based clinical settings, the wide availability of low cost and small semiconductor components, and the advancement of computer-based pulse wave analysis techniques. The PPG technology has been used in a wide range of commercially available medical devices for measuring oxygen saturation, blood pressure and cardiac output, assessing autonomic function and also detecting peripheral vascular disease. The introductory sections of the topical review describe the basic principle of operation and interaction of light with tissue, early and recent history of PPG, instrumentation, measurement protocol, and pulse wave analysis. The review then focuses on the applications of PPG in clinical physiological measurements, including clinical physiological monitoring, vascular assessment and autonomic function.

https://iopscience.iop.org/article/10.1088/0967-3334/28/3/R01/pdf

Photoplethysmography and its application in clinical physiological measurement.

William harvey, when studying the circulation of the blood, must have recognized that "In sound and living vessels the blood remains fluid, but it coagulates in dead ones" (Ernst Brucke, 1857). Joseph Lister (1909) provided further evidence for an active role of blood vessels in maintaining the liquidity of blood. The vascular endothelium, which envelops the circulating blood in a continuous monolayer, is mainly responsible for this function. Over the past 20 years numerous other important functions have been discovered. For instance, the outer surface of the endothelial cell contains angiotensin-converting enzyme, which catalyzes the formation of the vasoconstrictor angiotensin . . .

Regulatory functions of the vascular endothelium.

Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes

Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension due to the scleroderma spectrum of disease

Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial.

Pulmonary hypertension is characterized by progressive elevation of pulmonary artery pressure and vascular resistance, often leading to right ventricular failure and death (1-3). Continuous intravenous infusion of epoprostenol improves prognosis and symptoms in patients with primary (idiopathic) pulmonary hypertension (4-8). Randomized, controlled clinical trials of epoprostenol for secondary pulmonary hypertension have not been conducted. Pulmonary hypertension frequently complicates the scleroderma spectrum of disease, which includes diffuse scleroderma, limited scleroderma (the CREST syndrome [calcinosis cutis, the Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangectasia]), and the overlap syndrome. These multisystem diseases are characterized by connective tissue and vascular abnormalities; vascular lesions are prominent in all affected tissues (9). Pulmonary hypertension occurs in up to 33% of patients with diffuse scleroderma and 10% to 50% of those with the CREST syndrome (10, 11), in which it is one of the leading causes of death (12, 13). Pulmonary hypertension in the scleroderma spectrum of disease may be associated with interstitial pulmonary fibrosis or may consist of a direct involvement of small and medium-sized pulmonary arteries and arterioles with smooth-muscle hyperplasia, medial hypertrophy, and intimal proliferation (10, 13, 14). Principal involvement of the pulmonary vasculature is more common in the CREST syndrome, whereas patients with pulmonary hypertension and diffuse scleroderma more often have interstitial lung disease (13). No therapies have been proven effective for pulmonary hypertension secondary to the scleroderma spectrum of disease. Small numbers of patients have responded to captopril (15), nifedipine (16-20), and prazosin. In a short-term study of intravenous epoprostenol in seven patients with scleroderma (two with diffuse scleroderma and five with limited scleroderma), six had a decrease in mean pulmonary artery pressure and pulmonary vascular resistance (21). In a small study of pulmonary hypertension secondary to connective tissue disease, long-term infusion therapy with a prostacyclin analogue, iloprost, resulted in improvement in New York Heart Association (NYHA) functional class and quality of life but a variable hemodynamic response (22). Results from a single-center, uncontrolled study suggest that long-term, continuously infused epoprostenol therapy can produce hemodynamic and symptomatic responses in patients with connective tissue disease who have severe pulmonary hypertension that is refractory to conventional medical therapy (23). The rationale for using continuous epoprostenol infusion to treat pulmonary hypertension secondary to the scleroderma spectrum of disease was based on the efficacy of this therapy for primary pulmonary hypertension (4-8) and recognition that scleroderma is a disease characterized by vasospasm and structural changes in the walls of blood vessels. Prostacyclin is a naturally occurring substance produced by vascular endothelium that has vasodilating, antiplatelet aggregation, and cytoprotective effects (24-33). Endogenous production of prostacyclin is decreased in an animal model of neonatal pulmonary hypertension (34) and in adult humans with pulmonary hypertension (35). Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in patients with primary pulmonary hypertension (36). Endothelial dysfunction also plays an important role in the vascular manifestations of the scleroderma spectrum of disease (37, 38), including the Raynaud phenomenon and digital ischemia, which cause considerable morbidity. Calcium-channel blockers (39-45), enalapril (46), and intermittent intravenous infusions of prostacyclin (47-49) and iloprost (50-54) improve the Raynaud phenomenon in some patients. Mixed results have been obtained with oral prostacyclin analogues (55, 56), and a recent multicenter trial of oral iloprost showed no benefit (57). The effect of long-term, continuously infused epoprostenol on the severity of the Raynaud phenomenon and on digital ulcer counts has not been previously evaluated. Our 12-week multicenter, open-label, randomized study was designed to determine whether the beneficial effect of epoprostenol seen in patients with primary pulmonary hypertension could be extended to patients with pulmonary hypertension secondary to the scleroderma spectrum of disease. Our objective was to evaluate the effects of continuous infusion of epoprostenol on exercise capacity in patients with pulmonary hypertension secondary to the scleroderma spectrum of disease. A secondary objective was assessment of the effects of long-term continuous epoprostenol infusion on cardiopulmonary hemodynamics, Borg Dyspnea Score, Dyspnea-Fatigue Rating, NYHA functional class, survival, and safety. Vasospastic manifestations, such as the Raynaud phenomenon and digital ulcerations, were also followed. Methods Patient Selection Eligible patients had pulmonary hypertension secondary to the scleroderma spectrum of disease in accordance with the inclusion and exclusion criteria summarized in Table 1. For the purposes of this study, the scleroderma spectrum of disease was defined as systemic sclerosis with diffuse or limited scleroderma (58); systemic sclerosis that overlapped with another connective tissue disease; or the presence of definite features of systemic sclerosis, including the Raynaud phenomenon and positive test result for antinuclear antibody, plus positive test results for anticentromere antibody, anti-Scl 70 antibody, or nailfold capillary abnormalities. Systemic sclerosis with limited cutaneous involvement (the CREST syndrome) was defined as the presence of any three of the following conditions: subcutaneous calcinosis, the Raynaud phenomenon, esophageal dysfunction (defined clinically), sclerodactyly, or telangectasia. Patients with interstitial lung disease of a more than mild degree were not included in the study because such patients were thought to be less likely to show benefit. Table 1. Key Inclusion and Exclusion Criteria On the basis of a previous 12-week study of the effects of epoprostenol infusion in patients with severe primary pulmonary hypertension (6) and using the 6-minute walk test as the primary outcome measure, we calculated that 50 patients per treatment group would provide 80% power to detect a difference of 50 meters in the average change from baseline, at an level of 0.05 (two-tailed t-test). Randomization and Treatment The protocol was approved by the institutional review boards of the 17 participating centers. After giving informed consent, 111 eligible patients were randomly assigned (1:1) to receive continuous epoprostenol infusion (Flolan, Glaxo Wellcome, Inc., Research Triangle Park, North Carolina) plus conventional therapy or to receive conventional therapy alone. Investigators contacted a central randomization center to obtain treatment assignment, which was based on a stratified randomized block design. Assignments were stratified on the basis of vasodilator use at baseline (yes or no) and exercise capacity at baseline (50 to<200 m or 200 m) and were randomized within blocks. Fifty-six patients were assigned to receive epoprostenol plus conventional therapy, and 55 patients were assigned to receive conventional therapy alone. Investigators were not blinded to treatment group assignment; however, independent blinded observers assessed the primary efficacy measure, exercise capacity. Patients taking calcium-channel blockers at study entry continued to take them during the study period. Adjustments in concomitant medications were allowed during the study on the basis of clinical judgment. Patients in both groups were to receive oral anticoagulants during the study; 94 of the 111 enrolled patients took warfarin. Venous access for epoprostenol infusion (in the epoprostenol group only) was obtained by insertion of a permanent indwelling central venous catheter. Epoprostenol was infused continuously by a portable infusion pump (CADD-1 Model 5100 HF, SIMS Deltec, St. Paul, Minnesota). Patients were instructed in sterile technique, catheter care, and drug preparation and administration. Epoprostenol therapy was initiated at a low dose (usually 2 ng/kg of body weight per minute). During the 12-week study, doses were adjusted on the basis of signs or symptoms consistent with persistent pulmonary hypertension in the absence of intolerable adverse effects (Figure 1). Figure 1. Epoprostenol dosing. Outcome Measures The primary measure of efficacy was exercise capacity, as defined by the distance a patient could walk in 6 minutes. Trained observers at each site who were not otherwise involved in patient care administered the 6-minute walk test. All patients wore an ambulatory infusion pump and a hospital gown over their clothes to mask the presence or absence of a long-term indwelling catheter, thereby blinding testers to the patients' treatment groups. Each patient performed one practice walk test. A standardized, unencouraged 6-minute walk test was performed as described elsewhere (59) at baseline and at 1, 6, and 12 weeks. The 6-minute walk test has been shown to provide meaningful outcome data in assessing potential therapy for patients with pulmonary hypertension (6). Secondary measures of efficacy were cardiopulmonary hemodynamics measured by performing right-heart catheterization using standard techniques at baseline and week 12; the Borg Dyspnea Score (60), obtained immediately after completion of the 6-minute walk test at baseline and 1, 6, and 12 weeks (6, 59); the Dyspnea-Fatigue Rating, obtained before the 6-minute walk test at baseline and weeks 1, 6, and 12 (61); NYHA functional class (62), measured at baseline and weeks 1, 6, and 12; digital ulcer counts, done at baseline and weeks 6 and 12; and the severity of the Raynaud phenomenon, assessed 

Annals of Internal Medicine Continuous Intravenous Epoprostenol for Pulmonary Hypertension Due to the Scleroderma Spectrum of Disease

OBJECTIVE--To compare the long term effects of short term intravenous infusions of iloprost with those of oral nifedipine in patients with Raynaud9s phenomenon associated with systemic sclerosis. DESIGN--Double blind, placebo controlled, randomised group comparison. SETTING--Dermatology outpatient clinic. PATIENTS--Twenty three patients with Raynaud9s phenomenon associated with well documented systemic sclerosis (American Rheumatism Association criteria) and with typical abnormalities in fingernail folds on capillaroscopy. INTERVENTIONS--Twelve patients were randomised to receive intravenous infusions of iloprost starting at 0.5 ng/kg/min and increased by 0.5 ng/kg/min every 15 minutes to a maximum of 2.0 ng/kg/min for eight hours on three consecutive days with a further single infusion at week 8. Placebo capsules were given concurrently. Eleven patients were randomised to receive nifedipine, starting at 30 mg daily and increased to 60 mg daily after four weeks for another 12 weeks. Infusions of placebo were given in the same manner as the infusions of iloprost. One patient from each group withdrew because of social reasons and three patients receiving nifedipine withdrew because of side effects. END POINT--Reduction in number, duration, and severity of attacks of Raynaud9s phenomenon, reduction in number of digital lesions, increase in digital blood flow. MEASUREMENTS AND MAIN RESULTS--Measurements were taken at 0, 4, 8, 12, and 16 weeks. Both regimens produced a reduction in the number, duration, and severity of attacks of Raynaud9s phenomenon. The mean (SE) number of digital lesions was reduced with iloprost (from 3.5 (1.6) to 0.6 (0.3] and with nifedipine (from 4.3 (0.8) to 1.4 (0.5] after 16 weeks. Hand temperature and digital and microcirculatory blood flow were increased with iloprost but not with nifedipine. CONCLUSION--Both iloprost and nifedipine are beneficial in the treatment of Raynaud9s phenomenon. With nifedipine, however, side effects are common. Short term infusions of iloprost provide longlasting relief of symptoms, and side effects occur only during the infusions and are dose dependent.

https://www.bmj.com/content/bmj/298/6673/561.full.pdf

Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis: a double blind randomised study.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(99)04095-7.pdf

Effect of nitric-oxide-generating system on microcirculatory blood flow in skin of patients with severe Raynaud's syndrome: a randomised trial.

SUMMARY

Twenty five patients with Raynaud's phenomenon due to systemic sclerosis were infused with prostacyclin (PGI2). In 88% of the patients there was objective improvement, monitored by thermography or radiometry.

Treatment of Raynaud's phenomenon by intravenous infusion of prostacyclin (PGI2)

Twelve patients with systemic sclerosis (SS) and severe Raynaud's phenomenon received infusions of prostaglandin E1 (PGE1) at a dose of 6-10 ng/kg/min, with either saline or 5% dextrose, for 72 hours in a single-blind cross-over study. The infusions were administered intravenously by centrally positioned catheters. Infusions were well tolerated with only mild side effects. Following the PGE1 infusion cold tolerance improved and attacks of Raynaud's phenomenon were less frequent, less severe, and shorter in duration. This subjective improvement was maintained for several weeks in most patients, and 2 noted healing of ischaemic ulcers. There was no significant change in objective measurements of hand function after either infusion. However, pain measured on a 10 cm visual analogue scale improved 2.19 cm with PGE1 and only 0.91 cm with normal saline (P less than 0.05). Temperature of the fingers and hands recorded by thermography did not change significantly with saline infusions, but did rise during PGE1 infusions (mean rise 2.0 degrees C at 48 hours, p less than 0.001), and was maintained when measured again 2 weeks later (mean rise 1.56 degrees C, p less 0.001). PGE1 may therefore be suitable treatment for Raynaud's phenomenon and the vascular insufficiency of systemic sclerosis and other connective tissue diseases.

https://ard.bmj.com/content/annrheumdis/40/4/350.full.pdf

E.D. Cooke

Papers

Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis: a double blind randomised study.

Effect of nitric-oxide-generating system on microcirculatory blood flow in skin of patients with severe Raynaud's syndrome: a randomised trial.

Treatment of Raynaud's phenomenon by intravenous infusion of prostacyclin (PGI2)

Prostaglandin E1 infusions for vascular insufficiency in progressive systemic sclerosis.

Intravenous lignocaine in prevention of deep venous thrombosis after elective hip surgery.