Ophthalmologica, Basel 175: 309-320 (1977)
The Close Interrelationship between Increased Vascular Retinal Permeability and Blood Pressure Level. Evidence from Retinal Fluoroangiography P.T. Scarpelli, R.Brancato, U. Menchini, P. Santoro and S. Lamanna
The appearance on the ocular fundus of exudates, haemorrhages, oedema of the ret ina and of the optic disc, suggests a diag nosis of malignant hypertension. These ocu lar changes are usually associated with ex tremely high pressure levels (diastolic pres sure: 130 mm Hg or more). In human pathology we find at least two distinct conditions characterized by this as sociation. The first condition includes pa tients in which hypertension, whether en docrine or renovascular or essential, is the primary disease, and the accelerated or malignant phase is only a sequela of its course. These patients experience a critical pressure increase, while the kidney main tains at least in early stages a relative ana tomical and functional integrity. The plasma renin activity is generally high, and the vasoconstrictive component of hypertension seems to reach its maximum values [20]. Furthermore, at times it is rather difficult to keep pressure under control with con ventional medications, even in massive doses. Sometimes the effect of angiotensin antagonists is quite dramatic, but in extreme cases bilateral nephrectomy is required. On
the other hand, pressure control is always accompanied either by an arrest in the de cline of the renal function or by its im provement. The second condition regards those pa tients affected by primary nephropathy who, at a certain stage of the disease, develop a state of nitrogen retention with high pres sure levels, associated with the above-men tioned changes in the ocular fundus. These patients may never have been hypertensive, or were very moderately so, and the ap pearance of severe hypertension is to be considered mostly as a symptom connected with a renal failure in the regulation of body fluids |4, 5, 7, 8. 15], This failure may represent a transitory state related to a cause occasionally determined in the course of the disease and possibly reversible, or the terminal outcome of nephropathy. In the latter case, a periodical dialytic treat ment must be immediately carried out. The appearance of severe hypertension seems to be mainly determined by the volume com ponent (expansion of plasma volume) [15, 30], and hypertension usually is easily con trolled by anti-hypertensive drugs, but a
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/31/2018 6:44:31 AM
Department of Medicine and Ophthalmology. University of Florence, Florence, and Department of Ophthalmology. University of Trieste. Trieste
decrease in pressure values may be followed by a further decline of the renal function. From the physiological point of view, the most characteristic phenomenon asso ciated with severe hypertension in both con ditions consists of an increased vascular permeability, which can be directly appre ciated around the terminal retinal arterioles and the capillaries correlated with them by means of fluorescein angiography. Disorder ly vasomotor phenomena (vasospasm alter nated with vasodilation) involving more or less localized vasal segments are already evident when the arterial pressure is less elevated. Several experimental researches have been carried out on the relationship be tween pressure levels and the changes in vascular permeability [6, 11, 22]. The increase in vascular permeability in the cerebral and mesenteric vascular dis trict in animals during the development of hypertension was well documented cle visu by Byrom 16]. However, there is a shortage of data about man. In this study the se quence of changes in the permeability of the retinal vessels, related to short- and long-term pressure control in a group of patients representative of the above-men tioned conditions was evaluated fluoroangiographically.
Materials and Methods The group being evaluated included 7 males and 4 females between 20 and 59 years of age (average 32.7). Most of the subjects were admitted to the Department of Medicine after an outpa tient examination at the Department of Ophthal mology. where they had turned to following a loss of vision. All the patients met the current criteria for the diagnosis of malignant hyperten
sion. The ocular fundus revealed exudates, haem orrhages, various degrees of retinal and papil lary oedema, and the diastolic pressure was 130 mm Hg or more. In each case fluorescein angiography showed a localized or a diffused fluorescein leakage from the terminal retinal ar terioles and from the capillaries correlated with them. Five cases showed symptoms of hyper tensive encephalopathy, and 3 cases of heart failure. Informed consent to participate in the study was obtained from the patients. Each patient underwent an as thorough as possible diagnostic screening, which included the various tests for renal function, an evaluation of the haemodynamic pattern, plasma renin activity, descending pyel ography and. whenever necessary, renal arteriog raphy and biopsy. Blood pressure was taken five times a day, every 4 hrs. in the wake span (8.00. 12.00, 16.00. 20.00. 23.00). At the end of the screening, the patients could be thus subdivided: renovascular hyperten sion, I case; essential hypertension. 2 cases; pri mary aldosteronism. I case; lupoid nephritis, 2 cases; end-stage chronic glomerulonephritis. 6 cases (table I). The ascertained duration of hypertension in relation to the appearance of ocular symptoms varied between a maximum of 4 years and a minimum of a few days. At the time of admis sion. all patients underwent intramuscular or in travenous anti-hypertensive treatment, followed a few days after by oral therapy. Five patients required almost immediate extra-corporeal dial ysis. This was followed by a complete normaliza tion of blood pressure, and therefore all medica tions were suspended. A female patient (case 7) died 2 months after the beginning of periodical dialysis. In the two cases of lupoid nephritis, a renal failure and a critical increase in arterial pressure (diastolic pressure over 130 mm Hg) appeared quite suddenly at the end of a period of about I year, during which the patients had arbitrarily interrupted all forms of treatment. In these two cases, besides anti-hypertensive drugs, steroids and azathioprine were administered. Case I (bilateral stenosis of the renal artery) was successfully operated for revascularization of the right kidney after a month's medical treat
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/31/2018 6:44:31 AM
Scarpclli/Brancato/Menchini/Santoro/Lamanna
310
ment. After surgery, hypertension was more easily controlled, and smaller doses were required. In case 3 (primary aldosteronism) 200 mg spironolacton and 300 «g clonidine p.d. were suf ficient to keep pressure within normal limits be fore surgery. The drugs used in long-term treatment of cases I and 2 included clonidine and hydralazine, or /(-blocking and hydralazine, and diuretic doses and frequencies were chosen so that pressure levels would remain under control all day long. This could be established as patients were in structed to effect, after discharge, daily self measurements of blood pressure according to the above-mentioned schedule. The self-monitoring was interrupted only after making sure that pres sure was well controlled, and it was then sub stituted by daily measurements at random hours. Retinal fluorescein angiographies were carried out according to the current method, being fluo rescein dosed on the basis of body weight and glomerular filtration rate. The total number or retinal fluorescein angiograms for each case was in relation to the duration of the control period, which was interrupted only when fluorescein an giography showed no more fluorescein leakages, or when a complete restitutio ud integrum of the ocular fundus had been achieved. The interval between angiographies was chosen on the basis of (I) a lasting drop in arterial pressure, and (2) a preliminary retinography. The results of this study together with some of the patients' data are summarized in table II. An attempt has been made toward a quantitative evaluation of the changes in vascular caliber (arterioles) during treatment by means of a computerized elabora tion. An example is reported in figures. The de tails of this method are reported elsewhere |3|.
Discussion
Finneriy et ttl. [9] demonstrated that in normal subjects a severe acute increase in blood pressure - such as may be induced by the infusion of norepinephrine - is ac companied by a reduction in plasma volume and in total plasma protein mass. More recently, Purving et til. [251 confirmed this
311
result. They proved that even a moderately acute angiotensin-ll-induced hypertension, in normal subjects, can cause a reduction of plasma volume and an increase in the al bumin, and especially in the IgG and IgM transcapillary escape rate. Both these results seem to suggest an increase in vascular per meability. In these experiences a direct effect on permeability of the substances used to in duce hypertension could be excluded. As we must reasonably presume that the vascular system of the subjects examined was intact, hypertension should be considered the only factor responsible for this phenomenon. A change in vascular permeability, in terms of an increase both in transcapillary albumin escape rate [23,35] and in transglomerular albumin escape rate |24|, was found also in the untreated patients with moderate essential hypertension. In these patients, the increase in transcapillary al bumin escape rate appeared correlated with the pressure level and the anomaly disap peared almost completely when the pres sure level was well controlled [26|. The transglomerular albumin escape rate was equally affected by pressure normalization [24]. The methods used in this research do not permit the localization of permeability changes; although many reasons, mainly drawn from experimental researches, lead to believe that arterioles and capillaries are mostly involved [22]. With moderately high pressure levels, the increase in vascular permeability does not cause clinically appreciable signs (exu dates, proteinuria). Yet it was assumed to form the condition producing a ‘chronic, insidious and minimal leakage' of plasma components in the vessel walls [1|. In its turn, this would be responsible for the ac-
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/31/2018 6:44:31 AM
Increased Vascular Retinal Permeability and Blood Pressure Level
Scarpclli/Brancato/Menchini/Santoro/Lamanna
312
Table I
Case
Scx/age
Diagnosis
BP
GFR
Proteinuria
PRA* ng/ml/h
Retinal changes befluorés. leakage
haemorr.
1
sî/59
renovascular disease
270/135
46
1.4
3.720
++
4- 4-
2
The Close Interrelationship between Increased Vascular Retinal Permeability and Blood Pressure Level. Evidence from Retinal Fluoroangiography P.T. Scarpelli, R.Brancato, U. Menchini, P. Santoro and S. Lamanna
The appearance on the ocular fundus of exudates, haemorrhages, oedema of the ret ina and of the optic disc, suggests a diag nosis of malignant hypertension. These ocu lar changes are usually associated with ex tremely high pressure levels (diastolic pres sure: 130 mm Hg or more). In human pathology we find at least two distinct conditions characterized by this as sociation. The first condition includes pa tients in which hypertension, whether en docrine or renovascular or essential, is the primary disease, and the accelerated or malignant phase is only a sequela of its course. These patients experience a critical pressure increase, while the kidney main tains at least in early stages a relative ana tomical and functional integrity. The plasma renin activity is generally high, and the vasoconstrictive component of hypertension seems to reach its maximum values [20]. Furthermore, at times it is rather difficult to keep pressure under control with con ventional medications, even in massive doses. Sometimes the effect of angiotensin antagonists is quite dramatic, but in extreme cases bilateral nephrectomy is required. On
the other hand, pressure control is always accompanied either by an arrest in the de cline of the renal function or by its im provement. The second condition regards those pa tients affected by primary nephropathy who, at a certain stage of the disease, develop a state of nitrogen retention with high pres sure levels, associated with the above-men tioned changes in the ocular fundus. These patients may never have been hypertensive, or were very moderately so, and the ap pearance of severe hypertension is to be considered mostly as a symptom connected with a renal failure in the regulation of body fluids |4, 5, 7, 8. 15], This failure may represent a transitory state related to a cause occasionally determined in the course of the disease and possibly reversible, or the terminal outcome of nephropathy. In the latter case, a periodical dialytic treat ment must be immediately carried out. The appearance of severe hypertension seems to be mainly determined by the volume com ponent (expansion of plasma volume) [15, 30], and hypertension usually is easily con trolled by anti-hypertensive drugs, but a
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/31/2018 6:44:31 AM
Department of Medicine and Ophthalmology. University of Florence, Florence, and Department of Ophthalmology. University of Trieste. Trieste
decrease in pressure values may be followed by a further decline of the renal function. From the physiological point of view, the most characteristic phenomenon asso ciated with severe hypertension in both con ditions consists of an increased vascular permeability, which can be directly appre ciated around the terminal retinal arterioles and the capillaries correlated with them by means of fluorescein angiography. Disorder ly vasomotor phenomena (vasospasm alter nated with vasodilation) involving more or less localized vasal segments are already evident when the arterial pressure is less elevated. Several experimental researches have been carried out on the relationship be tween pressure levels and the changes in vascular permeability [6, 11, 22]. The increase in vascular permeability in the cerebral and mesenteric vascular dis trict in animals during the development of hypertension was well documented cle visu by Byrom 16]. However, there is a shortage of data about man. In this study the se quence of changes in the permeability of the retinal vessels, related to short- and long-term pressure control in a group of patients representative of the above-men tioned conditions was evaluated fluoroangiographically.
Materials and Methods The group being evaluated included 7 males and 4 females between 20 and 59 years of age (average 32.7). Most of the subjects were admitted to the Department of Medicine after an outpa tient examination at the Department of Ophthal mology. where they had turned to following a loss of vision. All the patients met the current criteria for the diagnosis of malignant hyperten
sion. The ocular fundus revealed exudates, haem orrhages, various degrees of retinal and papil lary oedema, and the diastolic pressure was 130 mm Hg or more. In each case fluorescein angiography showed a localized or a diffused fluorescein leakage from the terminal retinal ar terioles and from the capillaries correlated with them. Five cases showed symptoms of hyper tensive encephalopathy, and 3 cases of heart failure. Informed consent to participate in the study was obtained from the patients. Each patient underwent an as thorough as possible diagnostic screening, which included the various tests for renal function, an evaluation of the haemodynamic pattern, plasma renin activity, descending pyel ography and. whenever necessary, renal arteriog raphy and biopsy. Blood pressure was taken five times a day, every 4 hrs. in the wake span (8.00. 12.00, 16.00. 20.00. 23.00). At the end of the screening, the patients could be thus subdivided: renovascular hyperten sion, I case; essential hypertension. 2 cases; pri mary aldosteronism. I case; lupoid nephritis, 2 cases; end-stage chronic glomerulonephritis. 6 cases (table I). The ascertained duration of hypertension in relation to the appearance of ocular symptoms varied between a maximum of 4 years and a minimum of a few days. At the time of admis sion. all patients underwent intramuscular or in travenous anti-hypertensive treatment, followed a few days after by oral therapy. Five patients required almost immediate extra-corporeal dial ysis. This was followed by a complete normaliza tion of blood pressure, and therefore all medica tions were suspended. A female patient (case 7) died 2 months after the beginning of periodical dialysis. In the two cases of lupoid nephritis, a renal failure and a critical increase in arterial pressure (diastolic pressure over 130 mm Hg) appeared quite suddenly at the end of a period of about I year, during which the patients had arbitrarily interrupted all forms of treatment. In these two cases, besides anti-hypertensive drugs, steroids and azathioprine were administered. Case I (bilateral stenosis of the renal artery) was successfully operated for revascularization of the right kidney after a month's medical treat
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/31/2018 6:44:31 AM
Scarpclli/Brancato/Menchini/Santoro/Lamanna
310
ment. After surgery, hypertension was more easily controlled, and smaller doses were required. In case 3 (primary aldosteronism) 200 mg spironolacton and 300 «g clonidine p.d. were suf ficient to keep pressure within normal limits be fore surgery. The drugs used in long-term treatment of cases I and 2 included clonidine and hydralazine, or /(-blocking and hydralazine, and diuretic doses and frequencies were chosen so that pressure levels would remain under control all day long. This could be established as patients were in structed to effect, after discharge, daily self measurements of blood pressure according to the above-mentioned schedule. The self-monitoring was interrupted only after making sure that pres sure was well controlled, and it was then sub stituted by daily measurements at random hours. Retinal fluorescein angiographies were carried out according to the current method, being fluo rescein dosed on the basis of body weight and glomerular filtration rate. The total number or retinal fluorescein angiograms for each case was in relation to the duration of the control period, which was interrupted only when fluorescein an giography showed no more fluorescein leakages, or when a complete restitutio ud integrum of the ocular fundus had been achieved. The interval between angiographies was chosen on the basis of (I) a lasting drop in arterial pressure, and (2) a preliminary retinography. The results of this study together with some of the patients' data are summarized in table II. An attempt has been made toward a quantitative evaluation of the changes in vascular caliber (arterioles) during treatment by means of a computerized elabora tion. An example is reported in figures. The de tails of this method are reported elsewhere |3|.
Discussion
Finneriy et ttl. [9] demonstrated that in normal subjects a severe acute increase in blood pressure - such as may be induced by the infusion of norepinephrine - is ac companied by a reduction in plasma volume and in total plasma protein mass. More recently, Purving et til. [251 confirmed this
311
result. They proved that even a moderately acute angiotensin-ll-induced hypertension, in normal subjects, can cause a reduction of plasma volume and an increase in the al bumin, and especially in the IgG and IgM transcapillary escape rate. Both these results seem to suggest an increase in vascular per meability. In these experiences a direct effect on permeability of the substances used to in duce hypertension could be excluded. As we must reasonably presume that the vascular system of the subjects examined was intact, hypertension should be considered the only factor responsible for this phenomenon. A change in vascular permeability, in terms of an increase both in transcapillary albumin escape rate [23,35] and in transglomerular albumin escape rate |24|, was found also in the untreated patients with moderate essential hypertension. In these patients, the increase in transcapillary al bumin escape rate appeared correlated with the pressure level and the anomaly disap peared almost completely when the pres sure level was well controlled [26|. The transglomerular albumin escape rate was equally affected by pressure normalization [24]. The methods used in this research do not permit the localization of permeability changes; although many reasons, mainly drawn from experimental researches, lead to believe that arterioles and capillaries are mostly involved [22]. With moderately high pressure levels, the increase in vascular permeability does not cause clinically appreciable signs (exu dates, proteinuria). Yet it was assumed to form the condition producing a ‘chronic, insidious and minimal leakage' of plasma components in the vessel walls [1|. In its turn, this would be responsible for the ac-
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/31/2018 6:44:31 AM
Increased Vascular Retinal Permeability and Blood Pressure Level
Scarpclli/Brancato/Menchini/Santoro/Lamanna
312
Table I
Case
Scx/age
Diagnosis
BP
GFR
Proteinuria
PRA* ng/ml/h
Retinal changes befluorés. leakage
haemorr.
1
sî/59
renovascular disease
270/135
46
1.4
3.720
++
4- 4-
2
