[A man with a classic serious milk-alkali syndrome and a carcinoma of the stomach]. / Een man met een ernstig klassiek melk-alkalisyndroom en een maagcarcinoom.

A 42-year-old man was transferred to the Emergency Department after his friends had found him unresponsive and confused in his room. He had been experiencing upper abdominal complaints for a period of several months. He had taken large amounts of a calcium carbonate/magnesium subcarbonate preparation (Rennie) and had consumed at least 3 litres of dairy products per day. His behaviour was reported as being more and more abnormal during the previous few weeks. On admission he was confused and agitated and had involuntary movements of his limbs. Laboratory investigation indicated a triple acid base disorder, i.e. metabolic alkalosis, respiratory alkalosis and high anion gap metabolic acidosis, with severe dehydration. The metabolic alkalosis was caused by the intake of large amounts of dairy and antacids: milk-alkali syndrome. The metabolic acidosis was the result of hypovolaemia and pre-renal renal failure and the respiratory alkalosis was caused by hyperventilation due to the organic psychosyndrome. The patient was treated with volume expansion by isotonic saline and the administration of potassium and he was sedated with low-dose midazolam, which led to a full respiratory compensation of the metabolic alkalosis. A few days following admission, both the plasma calcium concentration and renal function returned to normal; the acid-base disorder completely normalized and the organic psychosyndrome disappeared. On gastroduodenoscopy a gastric ulcer was found; biopsies revealed a signet ring cell adenocarcinoma of the stomach.

5-HT, alpha-adrenoceptors, and blood pressure. Effects of ketanserin in essential hypertension and autonomic insufficiency.

The serotonin (5-hydroxytryptamine, 5-HT) antagonist, ketanserin, has a high affinity for 5-HT2-receptors but it also binds to alpha 1-adrenoceptors. The compound (10 mg i.v.) lowered mean arterial pressure by 22% +/- 2% (mean +/- SEM, p less than 0.001) in 30 patients with essential hypertension. Measurements of heart rate, cardiac output, cardiac filling pressures, forearm blood flow, renal blood flow, and glomerular filtration rate revealed a hemodynamic pattern compatible with vasodilation of both resistance and capacitance vessels. This was accompanied by moderate reflex cardiostimulation. Ketanserin did not alter the pressor effect of bolus injections of (-)-phenylephrine hydrochloride (25, 50, 100, and 200 micrograms i.v.). Ketanserin also had a distinct hypotensive effect in four normotensive patients with autonomic insufficiency due to an efferent sympathetic lesion, who were unresponsive to phentolamine (20 mg i.v.). Thus, ketanserin in the dose we have used appears to lower blood pressure independently of alpha 1-adrenoceptor blockade. On the other hand, in patients with essential hypertension the antihypertensive effect of ketanserin was blunted by pretreatment with prazosin (12 mg/day). Therefore, a certain degree of alpha 1-adrenergic tone seems to be required for the compound to exert its full antihypertensive action. The findings are indirect evidence for a role of 5-HT in the maintenance of increased vascular resistance in essential hypertension. This may be related, at least in part, to the alleged amplifying effect of 5-HT on alpha 1-adrenoceptor-mediated vasoconstriction.

Chronic effect of ketanserin in mild to moderate essential hypertension.

Ketanserin, an antagonist highly selective for 5-hydroxytryptamine (serotonin) type 2 (S2) receptors, was given as monotherapy in a dose of 40 mg b.i.d. to 24 subjects with mild to moderate essential hypertension. Its effects were evaluated in a placebo-controlled double-blind crossover study. The effect on blood pressure in 18 subjects was monitored by 24-hour ambulatory intra-arterial measurements. Systolic and diastolic intra-arterial pressures were significantly lowered by ketanserin both during the day and at night, whereas heart rate was unchanged. Cuff pressure readings (triplicate measurements) with the London School of Hygiene sphygmomanometer and an automatic device (12 measurements in 1 hour) in the outpatient clinic also showed a significant effect on both supine and standing pressures. No postural hypotension was noted. Ketanserin had no effect on endogenous creatinine clearance, serum cholesterol levels, and the plasma levels of norepinephrine, renin, and aldosterone. The only side effect that was significantly more common with ketanserin than with placebo treatment was an increase in body weight. Ketanserin may have a place in the treatment of mild to moderate essential hypertension.

Efficacy and tolerability of the renin inhibitor Ro 42-5892 in patients with hypertension.

The efficacy of multiple oral administration of the renin inhibitor Ro 42-5892 [(S)-alpha-](t-butylsulfonyl)-methyl]hydrocinnamamido]-N-[1S , 2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imi dazole-4- propionamide] was studied. Forty-nine patients with moderate essential hypertension were randomly assigned to three groups that entered an 8-day double-blind oral treatment period: daily administration of placebo (group A), 300 mg Ro 42-5892 (group B), or 600 mg Ro 42-5892 (group C). Four hours after the last oral drug intake, placebo was administered intravenously to subjects in group A and 100 mg Ro 42-5892 was administered intravenously to subjects in groups B and C. Sitting systolic and diastolic blood pressures were measured on days 1 and 8 with a blood pressure device. On day 1, systolic blood pressure maximally decreased by 13.3 +/- 9.3, 20.2 +/- 11.2, and 24.1 +/- 11.3 mm Hg in groups A, B, and C, respectively (mean +/- SD; p < 0.01 for group A versus group C). Diastolic blood pressure maximally decreased 9.4 +/- 5.7, 13.9 +/- 8.7, and 11.8 +/- 5.7 mm Hg (difference not significant). On day 8, systolic blood pressure maximally decreased 19.5 +/- 16.5, 26.5 +/- 17.4, and 30.5 +/- 18.4 mm Hg and diastolic blood pressure maximally decreased 14.8 +/- 5.0, 16.2 +/- 9.0, and 17.9 +/- 12.7 mm Hg (difference not significant) compared with pretreatment values. Intravenous drug administration did not further reduce blood pressure, suggesting that the mode of action and not the low bioavailability was the limiting factor for the low efficacy.

Hemodynamic and humoral effects of the novel calcium antagonist Ro 40-5967 in patients with hypertension.

The tolerability and hemodynamic and humoral effects of the structurally novel calcium antagonist Ro 40-5967 were investigated in 64 patients with hypertension. In a double-blind, placebo-controlled study, ascending oral doses of 50, 100, 150, or 200 mg were administered once daily for 8 days in a solution. Ro 40-5967 was well tolerated up to 150 mg, but treatment was stopped in one patient in the 200 mg group because of bradycardia. Blood pressure was dose-dependently reduced over the full 24-hour dosing period with more pronounced effects on day 8 than on day 1. The maximum blood pressure reduction was obtained after 150 mg (supine blood pressure, -34/-25 mm Hg, p less than 0.001). Despite a slight decrease in supine heart rate, cardiac output increased. PQ time was dose-dependently increased and concentration-effect analysis showed that relevant atrioventricular conduction disturbances occur only at concentrations much higher than those required to reduce blood pressure. Changes in catecholamines, plasma renin activity, and aldosterone were small and inconsistent. In conclusion, Ro 40-5967 has a long-lasting antihypertensive effect after once-daily administration.

Influence of haemodialysis on the pharmacokinetics and haemodynamic effects of nifedipine during continuous intravenous infusion.

The pharmacokinetics and haemodynamic effects of nifedipine were studied in 5 patients on long term haemodialysis. In addition, clearance of the drug on 2 different types of artificial kidneys were measured in vitro. Nifedipine was administered intravenously (1.3 mg/h) from 6 hours before starting haemodialysis to the end of haemodialysis, performed according to the standard protocol of each patient. Before and during haemodialysis, blood samples were taken for determination of free and total plasma nifedipine concentrations. Recovery was determined by measuring nifedipine concentrations in the dialysate. Heart rate and systolic and diastolic blood pressures were determined serially. The haemodynamic changes during nifedipine were compared with those of 3 previous dialysis sessions. Haemodialysis was accompanied by a slight decrease in steady-state nifedipine concentrations. The recovery in dialysate varied between 0.6 and 0.9% of the amount infused during the period of dialysis. Artificial kidney clearance of nifedipine varied between 2.8 and 8.3 ml/min, which was in agreement with in vitro data. Changes in steady-state nifedipine concentrations were most likely due to changes in systemic clearance caused by haemodialysis itself. Systolic and diastolic blood pressure dropped by approximately 15% and 25%, respectively, in comparison with dialysis without nifedipine, but changes in heart rate were not different. It is concluded that nifedipine is poorly dialysable. During haemodialysis, blood pressure is markedly reduced but dose schedules need not to be changed.

Resistance to antihypertensive medication as predictor of renal artery stenosis: comparison of two drug regimens.

BACKGROUND: Renal artery stenosis is among the most common curable causes of hypertension. The definitive diagnosis is made by renal angiography, an invasive and costly procedure. The prevalence of renal artery stenosis is less than 1% in non-selected hypertensive patients but is higher when hypertension is resistant to drugs. OBJECTIVE: To study the usefulness of standardised two-drug regimens for identifying drug-resistant hypertension as a predictor of renal artery stenosis. DESIGN AND SETTING: Prospective cohort study carried out in 26 hospitals in The Netherlands. PATIENTS: Patients had been referred for analysis of possible secondary hypertension or because hypertension was difficult to treat. Patients < or =40 years of age were assigned to either amlodipine 10 mg or enalapril 20 mg, and patients >40 years to either amlodipine 10 mg combined with atenolol 50 mg or to enalapril 20 mg combined with hydrochlorothiazide 25 mg. Renal angiography was performed: (1) if hypertension was drug-resistant, ie if diastolic pressure remained > or =95 mm Hg at three visits 1-3 weeks apart or an extra drug was required, and/or (2) if serum creatinine rose by > or =20 micromol/L (> or =0.23 mg/dL) during ACE inhibitor treatment. RESULTS: Of the 1106 patients with complete follow-up, 1022 had been assigned to either the amlodipine- or enalapril-based regimens, 772 by randomisation. Drug-resistant hypertension, as defined above, was identified in 41% of the patients, and 20% of these had renal artery stenosis. Renal function impairment was observed in 8% of the patients on ACE inhibitor, and this was associated with a 46% prevalence of renal artery stenosis. In the randomised patients, the prevalence of renal artery stenosis did not differ between the amlodipine- and enalapril-based regimens. CONCLUSIONS: In the diagnostic work-up for renovascular hypertension the use of standardised medication regimens of maximally two drugs, to identify patients with drug-resistant hypertension, is a rational first step to increase the a priori chance of renal artery stenosis. Amlodipine- or enalapril-based regimens are equally effective for this purpose.

The benefit of STent placement and blood pressure and lipid-lowering for the prevention of progression of renal dysfunction caused by Atherosclerotic ostial stenosis of the Renal artery. The STAR-study: rationale and study design.

BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is associated with progressive loss of renal function and is one of the most important causes of renal failure in the elderly. Current treatment includes restoration of the renal arterial lumen by endovascular stent placement. However, this treatment only affects damage caused by ARAS due to the stenosis and ensuing post-stenotic ischemia. ARAS patients have severe general vascular disease. Atherosclerosis and hypertension can also damage the kidney parenchyma causing renal failure. Medical treatment focuses on the latter. Lipid-lowering drugs (statins) could reduce renal failure progression and could reduce the overall high cardiovascular risk. The additional effect on preserving renal function of stent placement as compared to medical therapy alone is unknown. Therefore, the STAR-study aims to compare the effects of renal artery stent placement together with medication vs. medication alone on renal function in ARAS patients. METHOD: Patients with an ARAS of > or = 50% and renal failure (creatinine (Cr) clearance < 80 mL/min/1.73 m2) are randomly assigned to stent placement with medication or to medication alone. Medication consists of statins, anti-hypertensive drugs and antiplatelet therapy. Patients are followed for 2 yrs with extended follow-up to 5 yrs. The primary outcome of this study is a reduction in Cr clearance > 20% compared to baseline. This trial will include 140 patients.

Bicarbonate versus acetate hemodialysis in ventilated patients.

Hemodynamic tolerance to bicarbonate versus acetate hemodialysis was studied in seven ventilated, critically ill patients, suffering from acute renal failure. Both kinds of hemodialysis were carried out with a recirculating dialysate delivery system and a relatively low blood flow (180 ml/min). Each patient underwent two hemodialysis procedures, one with bicarbonate and one with acetate, lasting for four hours. Ultrafiltration rates were kept below 250 ml/h and only biocompatible membranes with a relatively small surface area (Biospal 2400, Hospal, France) were used. Despite the mild hemodialysis conditions, hypotensive episodes with a mean blood pressure below 70 mmHg were observed in 3 out of 7 bicarbonate sessions and 4 out of 7 acetate sessions. Thus, we could not demonstrate a hemodynamic advantage of bicarbonate hemodialysis in this group of ventilated patients. This contrasts with other studies conducted in non-ventilated patients. Prevention of hypoxemia by mechanical ventilation and control of vascular tone by the use of vasoactive drugs may be of more clinical relevance than the kind of hemodialysis procedure that is used.

A comparison of the safety and efficacy of mibefradil and nifedipine SR in patients with renal disease and hypertension.

The antihypertensive efficacy and safety of mibefradil and nifedipine SR were compared in 143 patients with chronic renal failure and mild-to-moderate hypertension in a multicenter, double-blind, randomized, parallel-design study. At treatment week 12, a significantly greater decrease in sitting diastolic blood pressure (SDBP) was seen with mibefradil than with nifedipine SR (12.8 mmHg vs 8.1 mmHg, respectively; p = 0.014). A significantly greater number of mibefradil-treated patients achieved normalization of SDBP by week 12 (62% vs 37%; p < 0.01). The changes in renal function parameters and the incidence of adverse events were similar in both groups. In this population, 12 weeks of treatment with mibefradil were more effective than nifedipine SR for lowering blood pressure and had similar effects on renal function parameters.

Betaxolol in obese hypertensive patients. Long-term effects on blood pressure and serum lipids.

The antihypertensive and metabolic effects of betaxolol (20 mg/day) were monitored in 40 patients (17 male), aged 54 +/- 2 yr (mean +/- SEM), with moderate essential hypertension. In a subgroup, consisting of 35 obese patients with a Quetelet index greater than 25.0, blood pressure, heart rate, side effects and biochemical variables were registered bi-monthly for a period of 6 months and after a placebo run-in and run-out period of 2 weeks. Betaxolol decreased blood pressure from 165 +/- 3/107 +/- 1 to 151 +/- 3/95 +/- 2 mmHg after 2 weeks and further to 151 +/- 3/93 +/- 2 mmHg after 6 months (p less than 0.001). Ninety percent of the patients responded to therapy with betaxolol. Heart rate fell from 77 +/- 2 to 64 +/- 1 bpm (p less than 0.001). No significant changes were observed in levels of total cholesterol, LDL-cholesterol or HDL-cholesterol. Triglycerides tended to increase from 2.2 +/- 0.3 to 2.8 +/- 0.4 mmol/l after 4 months of treatment (NS). Renal function was not influenced by betaxolol. Side effects, recorded on a standard questionnaire, did not differ between betaxolol and placebo. In conclusion, betaxolol in a fixed dose of 20 mg/day is an effective antihypertensive drug in the long-term treatment of obese, hypertensive patients, without adverse effects on lipoproteins.

Incidence and onset of critical illness polyneuropathy in patients with septic shock.

BACKGROUND: To estimate the incidence and onset of critical illness polyneuropathy (CIP) in patients in septic shock. METHODS: Prospective, observational study, no interventions, in a general 9-bed ICU of a large teaching hospital. Twenty-five patients consecutively admitted to the ICU for treatment of septic shock were studied. Within 72 h of admission to the ICU a complete neurological examination and electromyografic studies were done. Studies were repeated weekly until discharge of ICU or death or CIP confirmed. RESULTS: Nineteen patients developed CIP (76%), with a majority (80%) within 72 h after onset of septic shock. All twenty-two patients with multi organ dysfunction syndrome (MODS) had CIP. The three patients without MODS did not have CIP (P<0.01). CONCLUSIONS: In a group of patients suffering from septic shock the incidence of CIP is high (76%). The onset is early, within 72 h after onset of septic shock. CIP is an early feature of MODS, developing after septic shock.

Electrocardiographic changes in acute malaria.

In this report of two patients with acute malaria, the electrocardiogram on admission showed changes of repolarisation. In both cases these electrocardiographic changes normalised after anti-parasitic treatment. The first patient recovered completely; however, the second patient developed signs of congestive heart failure compatible with cardiomyopathy. In acute malaria, an electrocardiogram should be considered to detect myocardial involvement.

Ketanserin: haemodynamic effects and mechanism of action.

The haemodynamic effects of ketanserin, a compound with S2-serotonergic receptor and alpha 1-adrenoceptor blocking properties, are reviewed in patients with essential hypertension. The drug has a definite antihypertensive action, both acutely and chronically, and its haemodynamic profile is similar to that of a vasodilator acting on both arterioles and veins but with its main action on arterioles. Its vasodilator action is associated with little reflex cardiostimulation. Pressor responses to i.v. phenylephrine are not altered by therapeutic i.v. doses of ketanserin but pressor responses to methoxamine, a compound that is more specific for vascular alpha 1-receptors than phenylephrine, have been reported to be reduced after chronic oral treatment with ketanserin. However, chronic ketanserin, unlike the alpha 1-adrenoceptor antagonist, prazosin in therapeutic doses, caused no parallel shift of the dose-pressor response curve of methoxamine and the shift was very small compared with prazosin. Studies in patients with autonomic failure and virtually no endogenous alpha 1-adrenergic tone have substantiated that ketanserin is capable of lowering blood pressure independently of alpha 1-adrenoceptor blockade.