VASOPRESSOR AGENTS—Influence of Acidosis on Cardiac and Vascular Responsiveness

Clinical observations have indicated that patients who are in shock and who have coexisting acidosis respond relatively poorly to sympathomimetic amines. In experiments with dogs, it was found that, in the presence of acidosis, the pressor action of epinephrine, norepinephrine and metaraminol was considerably reduced. The effect on cardiac rhythm was also considerably lessened after the pH value of the blood had been lowered.In view of these observations in animals, six human patients with profound shock and acidosis were studied. All had a considerably lessened pressor response to vasopressor agents; then, after elevation of the blood pH by intravenous infusion of a 1-molar solution of sodium lactate, responsiveness was restored.These observations emphasize the desirability of close observation of the acid-base status, and early treatment of acidosis, as an important aspect in the management of patients with shock.     

Acid-base Balance in Acute Gastrointestinal Bleeding

Acid-base balance has been studied in 21 patients with acute upper gastrointestinal bleeding. A low plasma bicarbonate concentration was found in nine patients, accompanied in each case by a base deficit of more than 3 mEq/litre, indicating a metabolic acidosis. Three patients had a low blood pH. Hyperlactataemia appeared to be a major cause of the acidosis. This was not accompanied by a raised blood pyruvate concentration. The hyperlactataemia could not be accounted for on the basis of hyperventilation, intravenous infusion of dextrose, or arterial hypoxaemia. Before blood transfusion it was most pronounced in patients who were clinically shocked, suggesting that it may have resulted from poor tissue perfusion and anaerobic glycolysis. Blood transfusion resulted in a rise in lactate concentration in seven patients who were not clinically shocked, and failed to reverse a severe uncompensated acidosis in a patient who was clinically shocked. These effects of blood transfusion are probably due to the fact that red blood cells in stored bank blood, with added acid-citrate-dextrose solution, metabolize the dextrose anaerobically to lactic acid. Monitoring of acid-base balance is recommended in patients with acute gastrointestinal bleeding who are clinically shocked. A metabolic acidosis can then be corrected with intravenous sodium bicarbonate.     

Lacticacidosis: A Clinically Significant Aspect of Shock

A study was made of the metabolic acidosis of hypotensive shock in 25 patients in an attempt to elucidate its etiology and to determine if the degree of acidosis might be a good parameter for the evaluation of treatment and prognosis.Blood lactate was elevated (> 1.3 mEq./l.) in 24 of 25 patients in hypotensive shock. There was a good correlation (r= 0.83, p < 0.01) between rising blood lactate and decrease in serum bicarbonate and arterial pH, early in shock. These data indicate that the metabolic acidosis of early shock is largely due to lactate ion. Evidence is presented that high blood lactate levels early in shock are indicative of poor prognosis.     

Respiratory Insufficiency in Acute Myocardial Infarction

Arterial blood gases and pH were assessed in 115 patients who had suffered a myocardial infarction, with or without complicating cardiogenic shock or cardiac standstill. In 11 of the 78 uncomplicated cases and in 16 of the 37 complicated cases, the arterial O₂ tension was much lower than would be expected on the basis of a three-fold drop in cardiac output, indicating considerable right to left shunting. The death rate in the patients with uncomplicated myocardial infarction was 32% and that of the complicated cases 65%. In both groups it was greatest when the arterial pH was low, indicating that correction of the acidosis is essential. In many instances administration of 100% oxygen is inadequate to restore the oxygen tension to normal levels, and controlled ventilation may be necessary to maintain adequate alveolar ventilation. The findings indicate the necessity for repeated assessment of the arterial blood gas tensions and pH in any patient who has suffered a myocardial infarction. If the management of such patients is designed to provide adequate oxygenation, to maintain adequate alveolar ventilation and to correct the acid-base disturbances, the patient may be tided over the stage of “cardiac pump failure”.     

The Clinical Significance of Elevated Blood Lactate

Three patients with elevated blood lactate values are described. The first, despite moderate hyperlactatemia of 5.3 mEq./1. and severe acidosis with an arterial blood pH of 6.98, had no “excess lactate”. In a second patient, moderate acidosis with a pH of 7.27 and blood lactate of 7.5 mEq./1., of which 33% was excess lactate, was found to be secondary to tissue hypoxia on an ischemic basis and preceded the onset of clinical shock by four hours. A third patient, diabetic and under treatment with phenformin hydrochloride, presented with many features suggestive of pulmonary embolism, including marked pulmonary hypertension. A diagnosis of idiopathic lactic acidosis was established when the arterial blood pH was found to be 6.77 and a blood lactate value of 14.2 mEq./1., 60% as excess lactate, was discovered in the absence of a demonstrable cause of tissue hypoxia. Exploration of the pulmonary vascular bed showed no sign of mechanical blockage. The diagnostic, therapeutic and prognostic value of measuring blood lactic acid, and of quantitating the proportion circulating as “excess lactate”, is emphasized.     

Cryocrystalglobulinemia: pH-dependent precipitation of a monoclonal IgG-kappa-immunoglobulin

Cryoglobulinemia is seen in a minority of patients with plasma cell dyscrasias and can be of clinical relevance if intravascular gelling or precipitate formation occurs at low temperatures. We observed a patient suffering from IgG-kappa multiple myeloma which was complicated by instability of the immunoglobulin forming crystalline precipitates at low pH and low temperature. Short exposure to extreme cooling initiated an unusual course terminating in disseminated vascular occlusion and fatal outcome which was connected with an adverse effect of blood exchange. Crystal formation was noticed in anticoagulated blood samples even at 37 degrees C. In vitro studies showed a critical pH dependency of solubility of the immunoglobulin close to the physiological pH of the blood. These observations suggest that the fatal outcome was due to a vicious circle of ischemia, metabolic acidosis and intravascular precipitations, initiated not only by low acral temperatures but by cold-induced ischemic tissue acidosis as well. Serum of patients with monoclonal gammopathy and cryoglobulinemia should be tested for pH dependent immunoglobulin insolubility.     

Sympathetic innervation of the splanchnic region mediates the beneficial hemodynamic effects of 8-OH-DPAT in hemorrhagic shock

Administration of the 5-HT(1A) receptor agonist, 8-OH-DPAT, improves cardiovascular hemodynamics and tissue oxygenation in conscious rats subjected to hypovolemic shock. This effect is mediated by sympathetic-dependent increases in venous tone. To determine the role of splanchnic nerves in this response, effects of 8-OH-DPAT (30 nmol/kg iv) were measured following fixed-arterial blood pressure hemorrhagic shock (i.e., maintenance of 50 mmHg arterial pressure for 25 min) in rats subjected to bilateral splanchnic nerve denervation (SD). Splanchnic denervation decreased baseline venous tone as measured by mean circulatory filling pressure (MCFP) and accelerated the onset of hypotension during blood loss. Splanchnic denervation did not affect the immediate pressor effect of 8-OH-DPAT but did reverse the drug's lasting pressor effect, as well as its ability to increase MCFP and improve metabolic acidosis. Like SD, adrenal demedullation (ADMX) lowered baseline MCFP and accelerated the hypotensive response to blood withdrawal but also reduced the volume of blood withdrawal required to maintain arterial blood pressure at 50 mmHg. 8-OH-DPAT raised MCFP early after administration in ADMX rats, but the response did not persist throughout the posthemorrhage period. In a fixed-volume hemorrhage model, 8-OH-DPAT continued to raise blood pressure in ADMX rats. However, it produced only a transient and variable rise in MCFP compared with sham-operated animals. The data indicate that 8-OH-DPAT increases venoconstriction and improves acid-base balance in hypovolemic rats through activation of splanchnic nerves. This effect is due, in part, to activation of the adrenal medulla.     

A review of 126 Caesarean sections by blood gas and the acid-base status of newborn calves

Blood gas and acid-base status was determined in 126 Caesarean-derived calves. The newborn calves were assigned by venous blood pH value at birth to three groups as follows: Group 1 (normal): pH above 7.2; Group 2 (slight acidosis): pH 7.2 to 7.0; and Group 3 (severe acidosis): pH below 7.0. Following Caesarean section births 80 (63.5%) calves had normal acid-base values, while 30 (23.8%) had a slight acidosis, and 16 (12.7%) had severe acidosis. The degree of hypoxia was similar in each group. Six calves (37.5%) in Group 3 died within 48 h of birth. The blood gas and acid-base status of Caesarean-derived. calves was not significantly influenced by any examined parameters with the exception of sex in Groups 1 and 2. The occurrence of meconium-stained calves was 9.1% (n = 11), and only two calves were slightly or severely acidotic immediately after birth.     

Effects of indomethacin on postural hypotension in Parkinsonism.

A study was conducted to evaluate the effect of indomethacin on orthostatic hypotension in Parkinsonism. Twelve elderly patients participated and the drug was given in two-ways--as an intravenous infusion of 50 mg over 30 minutes and by mouth 50 mg thrice daily for six days. Results were assessed by measuring the degree of hypotension on standing, response to the cold pressor test, and forearm blood flow (by strain-gauge plethysmography). Indomethacin significantly reduced the fall in blood pressure on standing (P less than 0:001) and lessened or reversed orthostatic symptoms. Furthermore, there was an enhanced response to the cold pressor test and a reduction in forearm blood flow. These findings suggest that indomethacin has a positive effect on systemic vascular resistance.     

Lactic acidosis complicating treatment of ketosis of labour.

Hypertonic glucose, fructose, and sorbitol solutions were given intravenously to women in the first stage of labour who had ketonuria and ketonaemia as evidenced by a raised blood acetoacetate and 3-hydrosybutyrate. There was no difference in the antiketogenic action of these, which was rapid and effective, but when compared with a control group who were given normal saline they had a high incidence of hyperlactataemia, and nine out of 28 patients developed lactic acidosis after the infusions. The "lactatogenic" effect was shared by all three substrates, and when they are used in the treatment of ketosis of labour, and the mother develops lactic acidosis, they might exacerbate pre-existing lactic acidosis and precipitate fetal distress.     

Effect of air breathing on acid-base and ion regulation after exhaustive exercise and during low pH exposure in the bowfin, Amia calva.

To explore a potential conflict between air breathing and acid-base regulation in the bowfin (Amia calva), we examined how individuals with access to air differed from fish without air access in their response to acidosis. After exhaustive exercise, bowfin with access to air recovered significantly more slowly from the acidosis than fish without air access. While arterial blood pH (pH(a)) of fish without air access recovered to resting levels by 8 h, pH(a) was still significantly depressed in fish having access to air. In addition, Pco(2) was slightly more elevated in fish having air access than those without it. Fish with access to air still had a significant metabolic acid load after 8-h recovery, while those without air access completely cleared the load within 4 h. These results suggest that bowfin with access to air were breathing air and, consequently, were less able to excrete CO(2) and H(+) and experienced a delayed recovery. In contrast, during exposure to low pH, air breathing seemed to have a protective effect on acid-base status in bowfin. During exposure to low pH water, bowfin with access to air developed a much milder acidosis than bowfin without air access. The more severe acidosis in fish without air access was caused by an increased rate of lactic acid production. It appears that enhanced O(2) delivery allowed air-breathing bowfin to avoid acidosis-induced anaerobic metabolism and lactic acid production. In addition, during low pH exposure, plasma Na(+) and Cl(-) concentrations of fish without air access fell slightly more rapidly than those in fish with air access, indicating that the branchial ventilatory changes associated with air breathing limited, to some degree, ion losses associated with low pH exposure.     

Haematological, blood gas and acid-base effects of central histamine-induced reversal of critical haemorrhagic hypotension in rats.

In a rat model of volume-controlled irreversible haemorrhagic shock, which results in a severe metabolic acidosis and the death of all control animals within 30 min., intracerebroventricular injection of histamine (100 nmol) produces a prompt and long-lasting increase in mean arterial pressure and heart rate, with a 100% survival of 2 h after treatment. Histamine action is accompanied by a decrease in haematocrit value, haemoglobin concentration, erythrocyte and platelet count, and an increase in residual blood volume at the end of the experiment (2 h). Cardiovascular effects are also associated with a long-lasting rise in respiratory rate and biphasic blood acid-base changes - initial increase of metabolic acidosis with the decrease in arterial and venous pH, bicarbonate concentration and base excess, followed by almost a complete recovery of blood gas and acid-base parameters to the pre-bleeding values, with normalisation of arterial and venous pH, Pco2 bicarbonate concentration and base excess at the end of experiment. It can be concluded that in the late phase of central histamine-induced reversal of haemorrhagic hypotension there is almost a complete restoration of blood gas and acid-base status due to circulatory and respiratory compensations, while accompanying haematological changes are the result of the haemodilution and the increase in residual blood volume.     

In vivo 31P-NMR studies on energy metabolism in and catecholamine effect on rat liver during hypovolemic shock

In vivo 31P-NMR spectroscopy (31P-MRS) was used to study the metabolism of phosphate compounds in rat liver under various conditions. The changes in hepatic concentrations of ATP and inorganic phosphate (Pi) or intracellular pH (pHi) were monitored during hypovolemic shock with or without the infusion of catecholamines. Rapid decreases in the ATP level and pHi with a concomitant increase of Pi were observed upon induction of the hypovolemic shock. Dopamine infusion markedly improved the liver ATP concentration and intracellular acidosis, but epinephrine or norepinephrine were without effects. The present results suggest that dopamine increases abdominal blood flow and improves the energy metabolism in the liver during hypovolemic shock.     

The effects of different types of acidosis and extracellular calcium on the mechanical activity of turtle atria

Summary The effects of acidosis and extracellular calcium were examined at 20°C in the isolated spontaneously contracting atria of the freshwater turtle (Chrysemys picta bellii). The atria were subjected to treatments of lactic acidosis, hypercapnic acidosis or chloride acidosis in the presence of both normal (2.0 mM) and high (10.0 mM) calcium, which simulated levels of acidosis and calcium observed in vivo. In all cases of acidosis, pH was reduced to 6.80 from a control pH of 7.80.All three forms of acidosis significantly depressed the force of atrial contraction. During lactic and chloride acidosis a progressive decrease in contractile force was seen, while during hypercapnic acidosis a spontaneous partial recovery was observed following an initial sharp drop in tension. Hypercapnic acidosis had the most rapid effect on contractility, while chloride had the slowest effect.Elevated levels of calcium during lactic and hypercapnic acidoses significantly moderated the negative inotropic effects of acidosis, although contractile force was still below pre-acid values. During chloride acidosis with increased [Ca], no decline in contractile force was observed compared to the control values. Each of the three types of acidoses caused a significant decrease in the frequency of the spontaneous atrial contractions but this effect was not significantly improved with acidosis plus increased [Ca].Based on the present findings and on related observations of acidosis, it appears that the fresh-water turtle is able to compensate for the negative inotropic effects on the heart of both lactic and hypercapnic acidosis, and these compensations may contribute to its remarkable tolerance to anoxia.     

Lactic acidosis secondary to metformin overdose: a case report

ABSTRACT: INTRODUCTION: Metformin is a commonly used treatment modality in type 2 diabetes mellitus, with a welldocumented side effect of lactic acidosis. In the intensive care setting lactate and pH levelsare regularly used as a useful predictor of poor prognosis. In this article we highlight howhigh lactate levels are not an accurate predictor of mortality in deliberate metforminoverdose. CASE PRESENTATION: We present the case of a 70-year-old Caucasian man who took a deliberate metforminoverdose of unknown quantity. He had a profound lactic acidosis at presentation with a pH of6.93 and a lactate level of more than 20mmol/L. These figures would normally correspondwith a mortality of more than 80%; however, with appropriate management this patient'scondition improved. CONCLUSION: We provide evidence that the decision to treat severe lactic acidosis in deliberate metforminoverdose should not be based on arterial lactate and pH levels, as would be the case in otheroverdoses. We also demonstrate that appropriate treatment with hemodiafiltration and 8.4%sodium bicarbonate, even in patients with a very high lactate and low pH, can be successful.     

Markedly reduced blood pressure responsiveness in endotoxemic rats; reversal by neuropeptide Y

This study in conscious normotensive rats was performed to assess the effect of the vasoconstrictor peptide, neuropeptide Y (NPY), on blood pressure responsiveness to exogenous norepinephrine in endotoxaemia. NPY and endotoxin were infused at doses which had no effect on blood pressure, whether given alone or in combination. Endotoxin markedly reduced the pressor responses to bolus injections of norepinephrine. However, blood pressure responsiveness could be enhanced by infusing NPY simultaneously with the endotoxin. It is suggested that low dose NPY infusions may be clinically useful in reversing the reduced vascular responsiveness to pressor amines in shock.     

Veratrum viride; hypotensive and cardiac effects of intravenous use

The hypotensive action of veratrum viride given intravenously was studied in 24 patients, 22 of them hypertensive and 2 normotensive. Vasodepression of considerable but variable degree was obtained in all patients. Maximum hypotension occurred 8 to 15 minutes after injection and relative hypotension usually lasted at least two hours. In four patients subnormal hypotension occurred but there were no clinical manifestations of shock. The blood pressure rose promptly when pressor drugs were administered.A dose of 0.3 to 0.5 mg. brought about a satisfactory decrease in blood pressure. The degree of decrease was affected by the speed of administration and in a few patients by idiosyncratic sensitivity to the drug. Veratrum has an extravagal action on the pulse rate, and in that and other respects resembles digitalis. Veratrum should be given with caution to digitalized patients. Atropine reduced but did not abolish the hypotensive effect of veratrum, and was more effective when given before veratrum. This indicates that the parasympathomimetic action of veratrum is important in the mechanism of blood pressure reduction.     

Lactic Acidosis in Diabetes

Lactic acidosis is occasionally responsible for metabolic acidosis in diabetics. It may occur in the presence of normal blood levels of the ketone bodies, and such cases are often described as having “non-ketotic diabetic acidosis.” Lactic acid may contribute to the metabolic acidosis in patients with true diabetic ketoacidosis, but the blood lactate concentrations in these patients are not usually very high. In some patients the ketoacidosis is replaced by a lactic acidosis during treatment. This usually occurs in association with a serious underlying disorder and is associated with a poor prognosis. A transient increase in blood lactate concentration was in fact observed in most patients after the beginning of treatment, but the significance of this finding is uncertain.     

刺激腓深神经对低血压或休克狗心血管活动的影响

实验在麻醉狗中进行。静脉内匀速注射硝普钠时,平均动脉压和左心室收缩压明显降低,左心室dp/dt_(max)、-dp/dt_(max)和心力环面积均明显减小。此时电刺激一侧腓深神经可使动脉血压和左心室收缩压明显升高,dp/dt_(max)和心力环面积也显著增加。停止刺激后,动脉血压和左心室收缩压逐渐回向刺激前的水平。停止注射硝普钠5～15分钟后,上述各项观察指标基本恢复到注药前的水平。在用大肠杆菌内毒素造成休克的狗中,电刺激一侧腓深神经,也能使平均动脉压和左心室收缩压升高,同时dp/dt_(max)、-dp/dt_(max)和肠系膜血管阻力明显增高,但肾血管阻力增加不明显。本实验结果与以往的实验资料一起表明,在用扩血管药造成低血压时,躯体神经刺激引起的升压效应似乎以心肌收缩力增加为主;而在内毒素休克时,躯体神经刺激可通过改善心肌收缩功能和增加内脏血管阻力而引起升压作用。     

Clinical, metabolic, and genetic aspects of cytochrome C oxidase deficiency in Saguenay-Lac-Saint-Jean.

Thirty-four children with lactic acidosis and Leigh encephalopathy due to cytochrome C oxidase (COX) deficiency distributed in 28 families have recently been identified in northeastern Quebec, particularly in the Saguenay-Lac-Saint-Jean (SLSJ) region. The segregation analysis was consistent with an autosomal recessive mode of inheritance. The incidence was estimated at 1/2,063 live births between 1979 and 1990, and the carrier rate was estimated at 1/23 inhabitants in SLSJ. In SLSJ, the places of origin of the COX-deficient children and their parents did not show a clustered nonuniform distribution. The genealogical reconstruction of 54 obligate carriers identified 26 ancestors common to all of them. Twenty-two were 17th-century Europeans, suggesting that the COX-deficient gene was introduced in the French-Canadian population by early settlers. These results support the hypothesis of a founder effect for COX deficiency in northeastern Quebec. Clinical findings are reported for 15 of these COX-deficient patients, age 6 mo to 11 years. Moderate developmental delay, hypotonia, ataxia, strabismus, and mild facial dysmorphism were frequent. Eleven children died in episodes of fulminant metabolic acidosis. The patients had elevated blood and cerebrospinal fluid lactate levels, decreased blood bicarbonate levels, and normal blood pH. Leigh disease and microvesicular steatosis of the liver were present in all affected patients for whom postmortem examination was performed. This biochemically uniform group of patients showed a wide range of clinical severity.