Multicenter observational study comparing sedation/analgesia protocols for laser photocoagulation treatment of retinopathy of prematurity.

OBJECTIVE: The aim of this study was to identify the best sedation/analgesia protocol for laser photocoagulation (PC) of retinopathy of prematurity (ROP). STUDY DESIGN: This multicenter observational study included five hospitals, each using a specific sedation/analgesia protocol: local anesthesia with oxybuprocaine hydrochloride (Group L); intravenous pentazocine (Group P); intravenous fentanyl (Group F); air, oxygen and sevoflurane (AOS) inhalation (Group I). The groups were compared for pain responses, vital signs and adverse events. RESULTS: Heart rates and systemic blood pressures were elevated by PC in Groups L and P and Groups L, P and F, respectively. Moreover, poor analgesic efficacy was recognized in Groups L, P and F. In contrast, Group I experienced hypothermia, enteral feeding intolerance and apnea more frequently. CONCLUSION: From the viewpoint of sedation/pain relief, AOS anesthesia should be the best protocol. However, considering all the various factors together, the most reasonable one can be varied based on the patient's condition and hospital.

Digoxin-like immunoreactivity may contribute to hyperinsulinemia-associated hypertension in patients with glucose intolerance.

The role of endogenous digitalis-like factors in the pathogenesis of the hypertension associated with impaired glucose tolerance was investigated by measuring plasma digoxin-like immunoreactivity (DLI). Mean blood pressure correlated significantly with the obesity index, serum insulin-like immunoreactivity (IRI), and plasma DLI concentrations in subjects with impaired glucose tolerance (IGT). Plasma DLI concentrations also correlated significantly with the obesity index and serum IRI concentrations. Because increased insulin has been proposed to promote sodium reabsorption, sodium retention in turn has presumably caused an increase of natriuretic, digitalis-like factors reflected by the increased plasma DLI concentrations in patients with IGT. Consequently, increased DLI may contribute to the elevated arterial pressure in patients with hyperinsulinemia.

Digoxin-like immunoreactivity increases with intravenous infusion of saline in rats.

1. The effects of sodium-loading on releases of endogenous digitalis-like substance were investigated by measuring digoxin-like immunoreactivity (DLI) during intravenous infusions of isotonic (0.15 mol/L) and hypertonic (1 mol/L) saline in anaesthetized rats. Plasma DLI was measured after death by a digoxin-radioimmunoassay. 2. The infusion of isotonic saline and hypertonic saline elevated the central venous pressure to similar levels. The plasma DLI concentration in both the infused groups rose significantly compared with that in the control rat not receiving the intravenous infusion. 3. The difference in the hypothalamic concentrations of DLI was not significant among the three groups, however, there was a significant inverse relationship between the plasma and hypothalamic concentrations of DLI. 4. Results indicate that the central venous pressure, but not sodium concentration, is essentially involved in the release of DLI, possibly from the hypothalamus.

The effects of insulin and insulin-like materials in the brain on central cardiovascular regulation: with special reference to the central effects of sodium chloride.

The present study investigated the roles of insulin on central cardiovascular regulation. When rats were fed with a high-salt diet for 4 weeks, hypothalamic and pituitary contents of insulin-like immunoreactive substance (ILI) significantly decreased. The plasma concentration of ILI remained unaltered, however. Intracerebroventricular injections of insulin significantly decreased both the blood pressure and the heart rate, with corresponding decreases in renal sympathetic nervous activity in urethane-anesthetized rats. Microinjections of insulin into the ventromedial nucleus in the hypothalamus caused greater vasodepression and bradycardia compared with the intracerebroventricular injections. Intracerebroventricular infusions of insulin inhibited the pressor effects of simultaneously-infused hypertonic saline, and the digitalis-like immunoreactivity in both the plasma and the hypothalamus were significantly decreased by the insulin. These results indicate that ILI in the brain affects the central cardiovascular regulation through the suppression of both sympathetic nervous system activity and the release of digitalis-like substances. These mechanisms may operate particularly during a sodium load.

Chronic intracerebroventricular infusions of endothelin elevate arterial pressure in rats.

We investigated the effects of intracerebroventricular infusions of endothelin on cardiovascular and endocrinological responses using conscious, unrestrained rats. Chronic intracerebroventricular infusions of endothelin, 10 pmol/h for 7 days, elevated arterial pressure significantly on days 5, 6 and 7 of the infusion, compared with intracerebroventricular infusions of the vehicle. Heart rate decreased from day 1 of the infusion of endothelin until the end of the experiment. The urinary excretion of norepinephrine increased on day 3 and epinephrine increased on days 3, 4 and 5 of endothelin infusion. The urinary excretion of arginine vasopressin increased on day 5, 6 and 7 of the infusion. These findings suggest that chronic intracerebroventricular infusions of endothelin elicit elevations in arterial pressure and that the initiation of blood pressure rises can be related to sympathetic activation although the actual role for the pressor responses has been played by the released arginine vasopressin.

Intracerebroventricular infusions of insulin increase vasopressin release in rats.

1. The role of cerebral insulin or insulin-like immunoreactive substance (ILI) on arginine-vasopressin (AVP) release using rats was investigated. Feeding rats with a high salt diet for 4 weeks significantly decreased the contents of ILI in both the hypothalamus and pituitary gland. Intracerebroventricular infusions of insulin (4 and 40 micrograms/min for 30 min) increased plasma AVP concentrations dose-dependently without hypoglycaemia, but decreased hypothalamic and pituitary contents of AVP. 2. These results indicate that ILI in the brain may play a role in the secretion of AVP, and that this mechanism could be operated to control a water-sodium balance.

Intracerebroventricular injections of endothelin increase arterial pressure in conscious rats.

We investigated the possible effects of endothelin (ET) on the central regulation of arterial pressure by injecting ET intracerebroventricularly (ICV) into conscious rats. ICV injections of ET caused dose-dependent elevation of arterial pressure and increase of heart rate. The first reaction was abolished by bunazosin, an alpha 1-adrenergic blocker, injected intravenously. However, the increase in arterial pressure and heart rate caused the rats, injected with ET ICV, to roll to the left on their long axis for 20-30 min, followed by prolonged sedation. Furthermore, the pressor responses and tachycardia were significantly attenuated by the ICV pretreatment with nicardipine, a calcium channel blocker, and nicorandil, a nitrate derivative, respectively. These results suggest that ET may elevate the intracellular Ca2+ concentration ([Ca2+]i) of sympathetic nerve activity regulatory neurons of the brain, leading to an accelerated outflow of sympathetic nerve activity and cause the elevation of arterial pressure.

[Clinical investigation on the involvement of an endogenous digitalis-like substance in blood pressure regulation].

We assessed the role of circulating digitalis-like substance(s) on the blood pressure regulation in patients with essential hypertension, cardiac diseases, diabetes mellitus and renal diseases by measuring digoxin-like immunoreactivity (DLI). Plasma DLI concentrations tended to correlate with blood pressure in all patient groups. Plasma DLI correlated to plasma aldosterone concentration in patients with essential hypertension, which suggested close interrelationship between DLI and electrolytes metabolism with adrenal steroids. Serum immunoreactive insulin (IRI) levels significantly correlated with blood pressure. Because plasma DLI levels correlated with serum IRI, increased levels of insulin could have induced sodium retention leading to increased DLI levels. Digitalis-like substance, but not insulin, would have directly increased blood pressure in patients with abnormal glucose tolerance. Plasma DLI levels significantly correlated with the severity of renal insufficiency in patients with renal diseases. Plasma DLI highly correlated with amounts of plasma proteins, particularly with albumin, which would be due to the binding of DLI with albumin in plasma. Because the level of non-binding DLI is extremely low when assayed with a digoxin-radioimmunoassay, it was impossible to assess the level of a free-form of DLI, i.e., active DLI. That could be a reason why the correlation between the DLI and the other parameters was not highly significant. Collectively, these findings suggest that the DLI is one of the major determinants of blood pressure rises, regardless of any cause.

Digitalis-like substance is produced in the hypothalamus but not in the adrenal gland in rats.

We studied the role of the adrenals on the plasma levels and urinary output of the digoxin-like immunoreactivity in order to elucidate the interrelationship between the adrenals and hypothalamic digoxin-like immunoreactivity. Urine was collected for 24 h 6 days after the bilateral adrenalectomy and then rats were killed by decapitation. Urinary excretion of digoxin-like immunoreactivity did not differ significantly between the sham-operated and adrenalectomized groups, regardless of sodium intake. Plasma levels did not change significantly with sodium-loading, and adrenalectomy did not significantly affect the plasma concentrations of the immunoreactivity. However, bilateral adrenalectomy increased the content of digoxin-like immunoreactivity in the hypothalamus significantly in both rat groups fed with a regular (P less than 0.05) and a high-salt (P less than 0.02) diet. However, when the levels were measured only 16 h after bilateral adrenalectomy, both plasma and hypothalamic contents were significantly higher in the high-salt than the regular-salt group. The correlation between the plasma and hypothalamic content was significant (P less than 0.01). These results strongly suggest that digoxin-like immunoreactivity is produced in the hypothalamus but not in the adrenals, and that the adrenal glands influence the turnover of the hypothalamic endogenous digitalis-like substance.

Endogenous digitalislike substance in an adult population in Japan.

Possible involvement of an endogenous digitalislike substance (EDLS) in blood pressure regulation was investigated using a Japanese population. Mean arterial pressure (MAP) significantly correlated with urinary excretion of the EDLS, age, and the obesity index. The plasma EDLS correlated with urinary EDLS. Urinary EDLS excretion well correlated with the inhibitory activity on Na+,K+-ATPase, and also with the urinary excretion of NaCl. Obesity index correlated with the Na+,K+-ATPase inhibition and arterial pressure. Although plasma content of atrial natriuretic polypeptide correlated with the urinary Na+,K+-ATPase inhibition, it did not correlate with the rest of all parameters. Plasma vasopressin level did not correlate with these parameters either. These results clearly indicate that the circulating EDLS (ie, Na+,K+-ATPase inhibitor) is implicated in the hypertension associated with an excess intake of sodium, aging and obesity.

Vasopressor responses and hyperthermia by intracerebroventricular injections of penicillin, a pyrogen, in rats: involvement of brain angiotensin II.

Because hypothalamus is a center for both the blood pressure and thermoregulation, we assumed that there is a close interrelationship between them. To prove this hypothesis, effects of intracerebroventricular (ICV) injections of a pyrogen, penicillin-G (Pc), on the blood pressure and rectal temperature (RT) were investigated. The ICV injections increased the mean arterial pressure (MAP), heart rate (HR) and the abdominal sympathetic activity (SNA) dose-dependently in urethane-anesthetized rats. In conscious rats, Pc (100 U) elicited the two components of rises in MAP (+19 +/- 1 and +20 +/- 1 mm Hg), and both the RT and HR increased corresponding to the second phase of MAP responses (+1.0 +/- 0.1 degree C and +60 +/- 7 beats/min). ICV injections of an angiotensin II (ang II) antagonist significantly decreased the MAP (-30 +/- 4 mm Hg), HR (-106 +/- 13 beats/min), and the RT (-0.9 +/- 0.1 degree C). ICV injections of Pc elicited drinking behavior (the vehicle group; 1.1 ml/90 min vs Pc group; 8.6 ml) in rats water-deprivated for 24 hours. In spontaneously hypertensive rats (SHRs), ICV injections of Pc elicited augmented responses in the first phase but diminished in the second pressor phase. ICV injections of an ang II antagonist elicited augmented effects in both the MAP (-39 +/- 1 mm Hg) and RT (-0.8 +/- 0.1 degree C) in SHRs. Thus, RT fluctuated corresponding to the blood pressure level in the latter phase, where a brain ang II mechanism may be involved.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypothalamic digitalis-like substance is released with sodium-loading in rats.

Role of the hypothalamic digitalis-like substance (EDLS) on the hypertension associated with an excess intake of sodium and the releasing mechanism were investigated. The blood pressure in rats fed with a sodium diet increased significantly after 4 weeks of the treatment compared to the control rats fed with a regular diet, which was accompanied by increased urinary output of the EDLS. Electrical lesions of the AV3V area in the hypothalamus significantly decreased both the urinary EDLS level and the blood pressure elevated by the sodium-loading. With the immunohistochemistry using digoxin antibody, the immunoreactives were localized in the neurons of paraventricular and supraoptic nuclei and some other hypothalamic areas, and were also seen in the nerve fibers distributed in the basal hypothalamus, infundibulum, and pituitary posterior lobe. Assuming that the CSF sodium is responsible for the release of EDLS, hypertonic NaCl (2.5 M) was infused into the lateral ventricle for 30 minutes. Blood pressure increased gradually, attaining peak rises about 30 minutes later. The plasma content of the EDLS was significantly greater in the hypertonic NaCl group than the control group treated with either the artificial CSF or 2.5 M of urea solution. On the other hand, the hypothalamic content decreased with the infusion of the hypertonic saline. Furthermore, the continuous intracerebroventricular infusions of the hypertonic NaCl with osmotic minipumps in conscious rats significantly increased the arterial pressure after 6 days. Thereby, the plasma level of the EDLS was significantly greater than the control rats that received only the artificial CSF.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain renin-angiotensin system and the hypothalamic, digitalis-like Na+, K+-ATPase inhibitor in rats.

Since angiotensin (ang) II blockers attenuate the centrally-induced pressor responses to a Na+, K+-ATPase inhibitor, ouabain, a brain renin-ang system is assumed to be involved in this pressor mechanism. Centrally-induced pressor responses to hypertonic saline were also blocked with ang II blockers. Thereby, the increase in the plasma level of digoxin-like immunoreactivity was abolished with simultaneous infusions of an ang II analogue or atrial natriuretic polypeptide (ANP). These results indicate that the pressor responses to sodium salts are mediated via inhibition of the brain Na+, K+-ATPase, and that the brain renin-ang system is involved in this mechanism. We noted the existence of a digoxin-like immunoreactive substance (DLI) containing neurons in the hypothalamus (PVN, SON) with the fibers densely distributed in the AV3V area including OVLT, SFO and the median eminence, an area where receptors for ang II are also distributed (1,2). Since pressor responses to intracerebroventricular (ICV) infusions of hypertonic NaCl are abolished with ICV pretreatment with ang II blockers, a brain renin-ang system may be involved in this mechanism. We then searched for a possible relationship between the central effects of NaCl, a brain renin-ang system and an endogenous Na+, K+-ATPase inhibitor in the hypothalamus.