This is a very bad question, I will bet on one answer, but depending on data that we are not given, three answers could be valid. The trap is that they give us the initial clinical picture WITHOUT GASOMETRY and then they give us the blood gases afterwards WITHOUT CLINIC, so there is no way of knowing what the evolution of the patient has been with our treatment, so it is impossible to know what to do. If the patient initially came with a blood gas with a pH of 7.05 and now has the one we are given, we are doing well (although we are not told the time interval between one thing and the other) and, in this case, it could be worthwhile to continue with the same treatment. If nothing has evolved, the clinical picture is the same and the blood gas at the beginning was similar, something should be done (also depending on the patient's baseline status, which they do not tell us either). If we decide to do something, at present we might decide to use ventilation rather than theophylline, although with "so little" alteration of pH (and even more so if we think that this is a chronic patient who may have a baseline blood gas similar to the one presented to us) it may seem "exaggerated". We have nothing "against" theophylline (we are not told of any contraindication), but nowadays it is rare to resort to it. 1: Wrong, he is a "retentive" patient and increasing O2 flow is highly likely to increase hypercapnia and, therefore, acidosis. 2: We will keep this one as correct. 3: It is not a metabolic acidosis, the bicarbonate is not decreased, on the contrary, it is slightly increased trying to compensate the respiratory acidosis. 4: He does not reach respiratory failure by definition (pO2 60), but he has hypercapnia and slight acidosis. If we knew the first blood gas and she was much worse (i.e. she was doing very well), continuing with the same medication would be an option, but this data is missing!!!, in any case it seems to be a trick answer. 5: At present and -as already mentioned- taking into account that there is no formal contraindication, it is not usually used.

This is a very bad question, I will bet on one answer, but depending on data that we are not given, three answers could be valid. The trap is that they give us the initial clinical picture WITHOUT GASOMETRY and then they give us the blood gases afterwards WITHOUT CLINIC, so there is no way of knowing what the evolution of the patient has been with our treatment, so it is impossible to know what to do. If the patient initially came with a blood gas with a pH of 7.05 and now has the one we are given, we are doing well (although we are not told the time interval between one thing and the other) and, in this case, it could be worthwhile to continue with the same treatment. If nothing has evolved, the clinical picture is the same and the blood gas at the beginning was similar, something should be done (also depending on the patient's baseline status, which they do not tell us either). If we decide to do something, at present we might decide to use ventilation rather than theophylline, although with "so little" alteration of pH (and even more so if we think that this is a chronic patient who may have a baseline blood gas similar to the one presented to us) it may seem "exaggerated". We have nothing "against" theophylline (we are not told of any contraindication), but nowadays it is rare to resort to it. 1: Wrong, he is a "retentive" patient and increasing O2 flow is highly likely to increase hypercapnia and, therefore, acidosis. 2: [HIDDEN] 3: It is not a metabolic acidosis, the bicarbonate is not decreased, on the contrary, it is slightly increased trying to compensate the respiratory acidosis. 4: He does not reach respiratory failure by definition (pO2 60), but he has hypercapnia and slight acidosis. If we knew the first blood gas and she was much worse (i.e. she was doing very well), continuing with the same medication would be an option, but this data is missing!!!, in any case it seems to be a trick answer. 5: At present and -as already mentioned- taking into account that there is no formal contraindication, it is not usually used.

A patient previously diagnosed with COPD comes to the emergency room for 3 days with increased dyspnea until he is at rest, cough with whitish expectoration and marked drowsiness. After receiving treatment with oxygen at low concentrations, bronchodilators and coticoids, a second arterial blood gas with 28% inspiratory oxygen fraction shows a pH of 7.32, pO2 61 mmHg, pCO2 58 mmHg, HCO3- 29 mmol/l. What would be the interpretation you would make of the arterial blood gas and what treatment would you use?

Increase oxygen flow because he has acute respiratory acidosis and hypoxemia.

I would initiate noninvasive mechanical ventilation because he has acute hypercapnic respiratory failure with moderate respiratory acidosis.

I would add sodium bicarbonate to correct the acute metabolic acidosis.

The patient does not have respiratory insufficiency so he would continue with the same pharmacological regimen.

I would add intravenous aminophylline as a respiratory stimulant, since I appreciate hypoxemia and hypercapnia.

Non-invasive ventilation

COPD The most common indication for acute non-invasive ventilation is for acute exacerbation of chronic obstructive pulmonary disease. The decision to commence NIV, usually in the emergency department, depends on the initial response to medication (bronchodilators given by nebulizer) and the results of arterial blood gas tests. If after medical therapy the lungs remain unable to clear carbon dioxide from the bloodstream (respiratory acidosis), NIV may be indicated. Many people with COPD have chronically elevated CO2 levels with metabolic compensation, but NIV is only indicated if the CO2 is acutely increased to the point that the acidity levels of the blood are increased (pH<7.35). There is no level of acidity above which NIV cannot be started, but more severe acidosis carries a higher risk that NIV alone is not effective and that mechanical ventilation will be required instead.

Nasal high-flow oxygen <i>versus</i> noninvasive ventilation in acute exacerbation of COPD: protocol for a randomised noninferiority clinical trial.

Noninvasive ventilation (NIV) is considered as the first-line treatment for acute exacerbation of COPD (AECOPD) complicated by respiratory acidosis. Recent studies demonstrate a role of nasal high-flow oxygen (NHF) in AECOPD as an alternative treatment in patients intolerant to NIV or with contraindications to it. The study aimed to evaluate whether NHF respiratory support is noninferior compared to NIV in respect to treatment failure, defined as need for intubation or change to alternative treatment group, in patients with AECOPD and mild-to-moderate acute or acute-on-chronic hypercapnic respiratory failure. We designed a multicentre, prospective, randomised trial on patients with AECOPD, who have pH<7.35 but >7.25 and <iP</i <subaCO<sub2</sub</sub  >45 mmHg, in whom NIV is indicated as a first-line treatment. According to power analysis, 498 participants will be required for establishing noninferiority of NHF compared to NIV. Patients will be randomly assigned to receive NIV or NHF. Treatment will be adjusted to maintain <iS</i <subpO<sub2</sub</sub between 88%-92% for both groups. Arterial blood gases, respiratory variables, comfort, dyspnoea score and any pulmonary or extrapulmonary complications will be assessed at baseline, before treatment initiation, and at 1, 2, 4, 6, 12, 24, 48 h, then once daily from day 3 to patient discharge, intubation or death. Given the increasing number of studies demonstrating the physiological effects of NHF in COPD patients, we hypothesise that NHF respiratory support will be noninferior to NIV in patients with AECOPD and mild-to-moderate acute or acute on chronic hypercapnic respiratory failure.

Respiratory failure

Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise in arterial carbon dioxide levels is called hypercapnia. Respiratory failure is classified as either Type 1 or Type 2, based on whether there is a high carbon dioxide level, and can be acute or chronic. In clinical trials, the definition of respiratory failure usually includes increased respiratory rate, abnormal blood gases (hypoxemia, hypercapnia, or both), and evidence of increased work of breathing. Respiratory failure causes an altered mental status due to ischemia in the brain. The typical partial pressure reference values are oxygen Pa O2 more than 80 mmHg (11 kPa) and carbon dioxide Pa CO2 less than 45 mmHg (6.0 kPa). Cause

Oxygen therapy during exacerbations of chronic obstructive pulmonary disease.

Venturi masks (VMs) and nasal prongs (NPs) are widely used to treat acute respiratory failure (ARF) in chronic obstructive pulmonary disease (COPD). In this study, these devices were compared in terms of their potentiality to worsen respiratory acidosis and their capacity to maintain adequate (> 90%) arterial oxygenation (Sa,O2) through time (approximately 24 h). In a randomized cross-over study, 18 consecutive COPD patients who required hospitalization because of ARF were studied. After determining baseline arterial blood gas levels (on room air), patients were randomized to receive oxygen therapy through a VM or NPs at the lowest possible inspiratory oxygen fraction that resulted in an initial Sa,O2 of > or = 90%. Arterial blood gas levels were measured again 30 min later (on O2), and Sa,O2 recorded using a computer during the subsequent approximately 24 h. Patients were then crossed-over to receive O2 therapy by means of the alternative device (NPs or VM), and the same measurements obtained again in the same order. It was observed that both the VM and NPs improved arterial oxygen tension (p<0.0001) to the same extent (p=NS), without any significant effect upon arterial carbon dioxide tension or pH. However, despite this adequate initial oxygenation, Sa,O2 was < 90% for 3.7+/-3.8 h using the VM and for 5.4+/-5.9 h using NPs (p<0.05). Regression analysis showed that the degree of arterial hypoxaemia (p<0.05) and arterial hypercapnia (p<0.05) present before starting O2 therapy and, particularly, the initial Sa,O2 achieved after initiation of O2 therapy (p<0.0001) enabled the time (in h) that patients would be poorly oxygenated (Sa,O2 < 90%) on follow-up to be predicted. These findings suggest that, in order to maintain an adequate (> 90%) level of arterial oxygenation in patients with chronic obstructive pulmonary disease and moderate acute respiratory failure: 1) the initial arterial oxygen saturation on oxygen should be maximized whenever possible by increasing the inspiratory oxygen fraction; 2) this strategy seems feasible because neither the VM nor NPs worsen respiratory acidosis significantly; and 3) the Venturi mask (better than nasal prongs) should be recommended.

Respiratory acidosis

Diagnosis Diagnoses can be done by doing an ABG (Arterial Blood Gas) laboratory study, with a pH <7.35 and a PaCO2 >45 mmHg in an acute setting. Patients with COPD and other Chronic respiratory diseases will sometimes display higher numbers of PaCO2 with HCO3- >30 and normal pH. Terminology Acidosis refers to disorders that lower cell/tissue pH to < 7.35. Acidemia refers to an arterial pH < 7.36. See also Acidosis Alkalosis Arterial blood gas Chemical equilibrium pCO2 pH pKa Metabolic acidosis Metabolic alkalosis Respiratory alkalosis References External links Acid–base disturbances

Permissive hypercapnia

Permissive hypercapnia is hypercapnia (i.e. high concentration of carbon dioxide in blood) in respiratory insufficient patients in which oxygenation has become so difficult that the optimal mode of mechanical ventilation (with oxygenation in mind) is not capable of exchanging enough carbon dioxide. Carbon dioxide is a gaseous product of the body's metabolism and is normally expelled through the lungs. In acute respiratory distress syndrome (ARDS), decreasing the tidal volume on the ventilator (usually 6-8 mL/kg) to 4-6 mL/kg may decrease barotrauma by decreasing ventilatory peak airway pressures and leads to improved respiratory recovery. Hypercapnia (increased pCO2) sometimes needs to be tolerated in order to achieve these lower tidal volumes. The permissive hypercapnia leads to respiratory acidosis which might have negative side effects, but given that the patient is in ARDS, improving ventilatory function is more important.

Medical gas therapy

Patients with these conditions may suffer a range of symptoms including dyspnea (breathlessness), hypoxemia (below-normal oxygen content in the arterial blood) and eventually a weakening of the respiratory muscles due to exhaustion, which can lead to respiratory failure and require intubation and mechanical ventilation. Heliox may reduce all these effects, making it easier for the patient to breathe. Heliox has also found utility in the weaning of patients off mechanical ventilation, and in the nebulization of inhalable drugs, particularly for the elderly. Research has also indicated advantages in using helium–oxygen mixtures in delivery of anaesthesia. References Respiratory therapy Pulmonology Medical treatments Industrial gases

Intermittent short-term negative pressure ventilation and increased oxygenation in COPD patients with severe hypercapnic respiratory failure.

With the aim of testing a method that allows increasing concentrations of oxygen to be administered to patients with severe hypoxemia and hypercapnia while avoiding the risk of increasing respiratory acidosis, we studied 17 male patients with advanced chronic obstructive pulmonary disease (COPD) and severe hypercapnic respiratory failure. During 6 h and on one day only, all patients were given intermittent negative pressure ventilation (INPV) together with oxygenation starting at a concentration of 24 percent and increasing to 30 percent. Using this procedure, it was possible to raise arterial PaO2 to safe levels (from 47.2 +/- 3 mm Hg to 61.5 +/- 6 mm Hg, p less than 0.001) without increasing hypercapnia, and a significant drop in PaCO2 levels (from 74.4 +/- 9 mm Hg to 65.6 +/- 12 mm Hg, p less than 0.005) was even observed. One hour after INPV ended, the mean values of PaO2, PaCO2, oxygen saturation, and pH were also significantly better than prestudy values. We conclude that INPV and oxygen therapy with increasing oxygen flow could constitute an alternative option to intubation and mechanical ventilation in cases of severe hypercapnic respiratory failure due to advanced COPD.

InternalMed_Harrison

The most important group of patients who benefit from a trial of NIV are those with exacerbations of COPD and respiratory acidosis (pH <7.35). Experience from several randomized trials has shown that, in patients with ventilatory failure characterized by blood pH levels between 7.25 and 7.35, NIV is associated with low failure rates (15–20%) and good outcomes (as judged by intubation rate, length of stay in intensive care, and—in some series—mortality rates). In more severely ill patients with a blood pH <7.25, the rate of NIV failure is inversely related to the severity of respiratory acidosis, with higher failure rates as the pH decreases. In patients with milder acidosis (pH >7.35), NIV is not better than conventional treatment that includes controlled oxygen delivery and pharmacotherapy for exacerbations of COPD (systemic glucocorticoids, bronchodilators, and, if needed, antibiotics).

Alveolar–arterial gradient

Because A–a gradient is approximated as: (150 − 5/4(P)) – at sea level and on room air (0.21x(760-47) = 149.7 mmHg for the alveolar oxygen partial pressure, after accounting for the water vapor), the direct mathematical cause of a large value is that the blood has a low , a low Pa, or both. is very easily exchanged in the lungs and low Pa directly correlates with high minute ventilation; therefore a low arterial Pa indicates that extra respiratory effort is being used to oxygenate the blood. A low indicates that the patient's current minute ventilation (whether high or normal) is not enough to allow adequate oxygen diffusion into the blood. Therefore, the A–a gradient essentially demonstrates a high respiratory effort (low arterial Pa) relative to the achieved level of oxygenation (arterial ). A high A–a gradient could indicate a patient breathing hard to achieve normal oxygenation, a patient breathing normally and attaining low oxygenation, or a patient breathing hard and still

InternalMed_Harrison

Oxygen Supplemental O2 should be supplied to keep arterial saturations ≥90%. Hypoxemic respiratory drive plays a small role in patients with COPD. Studies have demonstrated that in patients with both acute and chronic hypercarbia, the administration of supplemental O2 does not reduce minute ventilation. It does, in some patients, result in modest increases in arterial PCO2, chiefly by altering ventilation-perfusion relationships within the lung. This should not deter practitioners from providing the oxygen needed to correct hypoxemia.

Hypercapnia

In many people a high causes a feeling of shortness of breath, but the lack of this symptom is no guarantee that the other effects are not occurring. A significant percentage of rebreather deaths have been associated with CO2 retention. The effects of high can take several minutes to hours to resolve once the cause has been removed. Diagnosis Blood gas tests may be performed, typically by radial artery puncture, in the setting of acute breathing problems or other acute medical illness. Hypercapnia is generally defined as an arterial blood carbon dioxide level over 45 mmHg (6 kPa). Since carbon dioxide is in equilibrium with carbonic acid in the blood, hypercapnia drives serum pH down, resulting in respiratory acidosis. Clinically, the effect of hypercapnia on pH is estimated using the ratio of the arterial pressure of carbon dioxide to the concentration of bicarbonate ion, . Tolerance

Respiratory acidosis

Types Respiratory acidosis can be acute or chronic. In acute respiratory acidosis, the PaCO2 is elevated above the upper limit of the reference range (over 6.3 kPa or 45 mm Hg) with an accompanying acidemia (pH <7.36). In chronic respiratory acidosis, the PaCO2 is elevated above the upper limit of the reference range, with a normal blood pH (7.35 to 7.45) or near-normal pH secondary to renal compensation and an elevated serum bicarbonate (HCO3− >30 mEq/L). Causes Acute Acute respiratory acidosis occurs when an abrupt failure of ventilation occurs. This failure in ventilation may be caused by depression of the central respiratory center by cerebral disease or drugs, inability to ventilate adequately due to neuromuscular disease (e.g., myasthenia gravis, amyotrophic lateral sclerosis, Guillain–Barré syndrome, muscular dystrophy), or airway obstruction related to asthma or chronic obstructive pulmonary disease (COPD) exacerbation.

Pulmonary gas pressures

The alveolar pO2 is not routinely measured but is calculated from blood gas measurements by the alveolar gas equation. Partial pressure of carbon dioxide Pathology The partial pressure of carbon dioxide, along with the pH, can be used to differentiate between metabolic acidosis, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis. Hypoventilation exists when the ratio of carbon dioxide production to alveolar ventilation increases above normal values – greater than 45mmHg. If pH is also less than 7.35 this is respiratory acidosis. Hyperventilation exists when the same ratio decreases – less than 35mmHg. If the pH is also greater than 7.45 this is respiratory alkalosis. See also Alveolar-arterial gradient Diffusing capacity Pulmonary alveolus References Respiratory physiology

Respiratory failure

This type of respiratory failure is caused by conditions that affect oxygenation, such as: Low ambient oxygen (e.g. at high altitude) Ventilation-perfusion mismatch (parts of the lung receive oxygen but not enough blood to absorb it, e.g. pulmonary embolism) Alveolar hypoventilation (decreased minute volume due to reduced respiratory muscle activity, e.g. in acute neuromuscular disease); this form can also cause type 2 respiratory failure if severe. Diffusion problem (oxygen cannot enter the capillaries due to parenchymal disease, e.g. in pneumonia or ARDS) Shunt (oxygenated blood mixes with non-oxygenated blood from the venous system, e.g. right to left shunt) Type 2 Hypoxemia (PaO2 <8kPa or normal) with hypercapnia (PaCO2 >6.0kPa). The basic defect in type 2 respiratory failure is characterized by: {| class="wikitable" |PaO2 || decreased (< )or normal |- | PaCO2 || increased (> ) |- | PA-aO2 || normal |- |pH || <7.35 |}

InternalMed_Harrison

Arterial blood gas testing is often helpful in assessing respiratory 1663 disease. Hypoxemia, while usually apparent with pulse oximetry, can be further evaluated with the measurement of arterial PO2 and the calculation of an alveolar gas and arterial blood oxygen tension difference ([A–a]DO2). Patients with diseases that cause ventilation-perfusion mismatch or shunt physiology have an increased (A–a) DO2 at rest. Arterial blood gas testing also allows the measurement of arterial PCO2. Hypercarbia can accompany severe airway obstruction (e.g., COPD) or progressive restrictive physiology, as in patients with neuromuscular weakness.

Noninvasive Ventilation -- Clinical Significance -- Clinical Pearls

Start treatment as early as possible When arterial pH is less than 7.35 and elevated PaCO2, it indicates the presence of acute or acute on chronic hypercapnia respiratory failure, which require admission to ICU In acute on chronic hypercapnia respiratory failure, the first goal is to correct arterial pH In chronic hypercapnic respiratory failure with arterial PaCO2more than 51 mmHg, the use of high-intensity pressure support is indicated. It should be targeted to correct CO2 toward normal or at least reduced by 20% from initial levels. When OSA is suspected, the EPAP  should be adjusted empirically (use the 10% rule of actual body weight) if no PAP titration was performed.

Oxygen therapy

Careful titration of oxygen therapy should be considered in patients with chronic conditions predisposing them to carbon dioxide retention (e.g., COPD, emphysema). In these instances, oxygen therapy may decrease respiratory drive, leading to accumulation of carbon dioxide (hypercapnia), acidemia, and increased mortality secondary to respiratory failure. Improved outcomes have been observed with titrated oxygen treatment largely due to gradual improvement of the ventilation/perfusion ratio. The risks associated with loss of respiratory drive are far outweighed by the risks of withholding emergency oxygen, so emergency administration of oxygen is never contraindicated. Transfer from the field to definitive care with titrated oxygen typically occurs long before significant reductions to the respiratory drive are observed. Contraindications There are certain situations in which oxygen therapy has been shown to negatively impact a person's condition.

Hypocarbia -- Treatment / Management

Treatment of hypocapnia is targeted at treating the underlying pathology to reduce the respiratory rate if possible. Historically treatment involved rebreathing into a paper bag to increase alveolar CO2. However, this has been shown to increase undesirable outcomes including mortality, and is no longer recommended. In anxious patients, anxiolytics may be necessary. In an infectious disease, antibiotics targeting sputum or blood cultures are appropriate. In embolic disease, anticoagulation is necessary. Ventilator support may be necessary for patients with acute respiratory failure, acute asthma, or acute COPD exacerbation if they show signs of respiratory fatigue. In ventilator-controlled patients, it may be necessary to reevaluate their ventilator settings to reduce respiratory rate. If hyperventilation is intentional, monitor the arterial or venous blood gas values closely. In severe cases, pH may be directly reduced using acidic agents; however, this is not routinely performed. [11]

Hypercapnia

At higher concentrations of CO2, unconsciousness occurred almost instantaneously and respiratory movement ceased in 1 minute. After a few minutes of apnea, circulatory arrest was seen. These findings imply that the cause of death in breathing high concentrations of CO2 is not the hypoxia but the intoxication of carbon dioxide. Treatment The treatment for acute hypercapnic respiratory failure depends on the underlying cause, but may include medications and mechanical respiratory support. In those without contraindications, non-invasive ventilation (NIV) is often used in preference to invasive mechanical ventilation. In the past, the drug doxapram (a respiratory stimulant), was used for hypercapnia in acute exacerbation of chronic obstructive pulmonary disease but there is little evidence to support its use compared to NIV, and it does not feature in recent professional guidelines.

Heliox

Patients with these conditions may suffer a range of symptoms including dyspnea (breathlessness), hypoxemia (below-normal oxygen content in the arterial blood) and eventually a weakening of the respiratory muscles due to exhaustion, which can lead to respiratory failure and require intubation and mechanical ventilation. Heliox may reduce all these effects, making it easier for the patient to breathe. Heliox has also found utility in the weaning of patients off mechanical ventilation, and in the nebulization of inhalable drugs, particularly for the elderly. Research has also indicated advantages in using helium–oxygen mixtures in delivery of anaesthesia. Diving uses Owing to the expense of helium, heliox is most likely to be used in deep commercial diving. It is also sometimes used by diving enthusiasts, particularly those using rebreathers, which conserve the breathing gas at depth much better than open circuit scuba.

[Non-invasive ventilation support in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD)].

To verify that the use of noninvasive ventilatory support in acute exacerbation of chronic obstructive pulmonary disease leads to decreasing the number of deaths, shortening in-hospital stay and decreasing number of endotracheal intubations (ETI). The study was conducted at a respiratory department's ICU in 2002-2004. Patients hospitalized on ICU with acute exacerbation of COPD, respiratory acidosis and global respiratory failure were randomised into two groups. Patients in group A were treated by conservative medical therapy (oxygen, bronchodilator, corticosteroid), patients in group B received noninvasive ventilation with face mask. The parameters followed were: decrease in the number of deaths, shortening of ICU stay, reduction of ETI, faster improvement of breathing frequency, heart rate, pH, PaO2, PaCO2, lactate, dyspnoea symptom score and lung functions. Each group consisted of 30 randomised patients. There were 10 intubated patients in group A, as opposed to 3 in group B (N = 60; P = 0.034). Average length of ICU stay was 9.8 days in group A and 7.1 days in group B (N = 60; P = 0.756). Mortality rate was identical in both groups: 3 patients survived, 7 patients died. We found faster decrease of breathing frequency after one hour of noninvasive ventilation in group B (28.3 +/- 7.1 vs. 24.6 +/- 6.3, N = 59, p = 0.03). No difference was found in mortality rate. We observed decreasing of ETI rate with NIV. We found a tendency to shortening of ICU stay. There was faster improvement of breathing frequency after one hour of NIV.

[The influence of oxygen therapy on the hypercapnia in patients with chronic obstructive pulmonary disease].

Oxygen therapy is a necessary therapeutic method in treatment of severe chronic respiratory failure (CRF), especially in phases of acute worsening. Risks which are to be taken into consideration during this therapy are: unpredictable increase of carbon dioxide in blood, carbonarcosis, respiratory acidosis and coma. The aim of this study was to show the influence of oxygen therapy on changes of arterial blood carbon dioxide partial pressure. The study included 93 patients in 104 admittances to the hospital due to acute exacerbation of CFR. The majority of the patients (89.4%) had chronic obstructive pulmonary disease (COPD), while other causes of respiratory failure were less common. The effect of oxygenation was controlled through measurement of PaO2 and PaCO2 in arterial blood samples. To analyse the influence of oxygen therapy on levels of carbon dioxide, greatest values of change of PaO2 and PaCO2 values from these measurements, including corresponding PaO2 values from the same blood analysis were taken. The obtained results show that oxygen therapy led to the increase of PaO2 but also to the increase of PaCO2. The average increase of PaO2 for the whole group of patients was 2.42 kPa, and the average increase of PaCO2 was 1.69 kPa. There was no correlation between the initial values of PaO2 and PaCO2 and changes of PaCO2 during the oxygen therapy. Also, no correlation between the produced increase in PaO2 and change in PaCO2 during this therapy was found. Controlled oxygen therapy in patients with severe respiratory failure greately reduces the risk of unwanted increase of PaCO2, but does not exclude it completely. The initial values of PaO2 and PaCO2 are not reliable parameters which could predict the response to oxygen therapy.

PCO2

Medicine In medicine, the partial pressure of carbon dioxide in arterial blood is called or PaCO2. Measurement of in the systemic circulation indicates the effectiveness of ventilation at the lungs' alveoli, given the diffusing capacity of the gas. It is a good indicator of respiratory function and the closely related factor of acid–base homeostasis, reflecting the amount of acid in the blood (without lactic acid). Normal values for humans are in the range 35–45 mmHg. Values less than this may indicate hyperventilation and (if blood pH is greater than 7.45) respiratory alkalosis. Values greater than 45 mmHg may indicate hypoventilation, and (if blood pH is less than 7.35) respiratory acidosis. Aquatic Sciences

Respiratory acidosis

Acute respiratory acidosis: HCO3− increases 1 mEq/L for each 10 mm Hg rise in PaCO2. Chronic respiratory acidosis: HCO3− rises 3.5 mEq/L for each 10 mm Hg rise in PaCO2. The expected change in pH with respiratory acidosis can be estimated with the following equations: Acute respiratory acidosis: Change in pH = 0.08 X ((40 − PaCO2)/10) Chronic respiratory acidosis: Change in pH = 0.03 X ((40 − PaCO2)/10) Respiratory acidosis does not have a great effect on electrolyte levels. Some small effects occur on calcium and potassium levels. Acidosis decreases binding of calcium to albumin and tends to increase serum ionized calcium levels. In addition, acidemia causes an extracellular shift of potassium, but respiratory acidosis rarely causes clinically significant hyperkalemia. Diagnosis

Glomus cell

Function Glomus type I cells are chemoreceptors which monitor arterial blood for the partial pressure of oxygen (pO2), partial pressure of carbon dioxide (pCO2) and pH. Glomus type I cells are secretory sensory neurons that release neurotransmitters in response to hypoxemia (low pO2), hypercapnia (high pCO2) or acidosis (low pH). Signals are transmitted to the afferent nerve fibers of the sinus nerve and may include dopamine, acetylcholine, and adenosine. This information is sent to the respiratory center and helps the brain to regulate breathing.

[Indications and contraindications for oxygen therapy of respiratory insufficiency].

After a critical review of the different opinions, the author differentiates the indications for oxygen treatment of respiratory insufficiency to subjective and objective based on his own experience following a clinical observation of 100 patients with exacerbated chronic respiratory insufficiency, subjected to dosed, controlled and continuous oxygen therapy. The most essential objective indication for oxygen treatment is the manifestation of hypoxemia degree without or with CO2 retention. According to hypoxemia manifestation, determined by PaO2 level, the indications are absolute (with PaO2 under 40 mm Hg), urgent (with PaO2 under 30 mm Hg) and relative (with PaO2 over 50 mm Hg). The application of oxygen treatment with PaO2 over 700 mm Hg as well as the so called "preventive" O2 treatment (with no hypoxemia) is improper with a view to possible harmful side effects of oxygen. Oxygen treatment is contraindicated in all patients with unfavourable ventilation response to oxygen treatment. In case of non-effective O2 treatment (unfavourable ventilation response resp.) mechanical ventilation must be turned to as well as in all cases with patients in respiratory coma.

InternalMed_Harrison

The management of respiratory acidosis depends on its severity and rate of onset. Acute respiratory acidosis can be life-threatening, and measures to reverse the underlying cause should be undertaken simultaneously with restoration of adequate alveolar ventilation. This may necessitate tracheal intubation and assisted mechanical ventilation. Oxygen administration should be titrated carefully in patients with severe obstructive pulmonary disease and chronic CO2 retention who are breathing spontaneously (Chap. 314). When oxygen is used injudiciously, these patients may experience progression of the respiratory acidosis. Aggressive and rapid correction of hypercapnia should be avoided, because the falling PaCO2 may provoke the same complications noted with acute respiratory alkalosis (i.e., cardiac arrhythmias, reduced cerebral perfusion, and seizures). The PaCO2 should be lowered gradually in chronic respiratory acidosis, aiming to restore the PaCO2 to baseline levels and to provide

Metabolic alkalosis

To calculate the expected pCO2 in the setting of metabolic alkalosis, the following equations are used: pCO2 = 0.7 [HCO3] + 20 mmHg ± 5 pCO2 = 0.7 [HCO3] + 21 mmHg Treatment To effectively treat metabolic alkalosis, the underlying cause(s) must be corrected. A trial of intravenous chloride-rich fluid is warranted if there is a high index of suspicion for chloride-responsive metabolic alkalosis caused by loss of gastrointestinal fluid (e.g., due to vomiting). Terminology Alkalosis refers to a process by which the pH is increased. Alkalemia refers to a pH which is higher than normal, specifically in the blood. See also Hypokalemia Metabolic acidosis Respiratory acidosis Respiratory alkalosis References External links Acid–base disturbances

[Noninvasive ventilation and acute respiratory failure].

Noninvasive ventilation is effective in acute respiratory failure, in which drug therapy and administration of supplemental oxygen do not suffice and attempts are made to prevent the patient from ending up in invasive respirator therapy. The treatment is suited for acute respiratory failure for instance in cases of exacerbation of chronic obstructive pulmonary disease, in which a disturbance of pulmonary ventilation leads to the accumulation of carbon dioxide and to respiratory acidosis. Disadvantages associated with artificial airways are avoided, number of complications are reduced, hospitalization periods become shorter, mortality decreases and costs are saved.

Hyperoxia

Diagnosis Treatment Oxygen supplementation is used to treat tissue hypoxia and to relieve arterial hypoxemia. High concentrations of oxygen are often given to patients with chronic obstructive pulmonary disease (COPD) or acute lung injury (ALI). Supplementing oxygen is known to cause tissue damage, with toxicity increasing with the increase of oxygen concentrations and exposure pressures. Unfortunately, the supplementation of oxygen is necessary if an individual is not able to obtain sufficient oxygen through respiration and perfusion. To decrease the chances of hyperoxia, the therapist should use the lowest concentration of oxygen required by an individual. At this time, there are no known alternatives to oxygen supplementation. See also References Oxygen Respiratory diseases Diving medicine

Acidosis

Mutations to the V-ATPase 'a4' or 'B1' isoforms result in distal renal tubular acidosis, a condition that leads to metabolic acidosis, in some cases with sensorineural deafness. Arterial blood gases will indicate low pH, low blood HCO3, and normal or low PaCO2. In addition to arterial blood gas, an anion gap can also differentiate between possible causes. The Henderson-Hasselbalch equation is useful for calculating blood pH, because blood is a buffer solution. In the clinical setting, this equation is usually used to calculate HCO3 from measurements of pH and PaCO2 in arterial blood gases. The amount of metabolic acid accumulating can also be quantitated by using buffer base deviation, a derivative estimate of the metabolic as opposed to the respiratory component. In hypovolemic shock for example, approximately 50% of the metabolic acid accumulation is lactic acid, which disappears as blood flow and oxygen debt are corrected. Treatment


He already takes two AV node brakers and you add a third, and are you surprised that he gets complete AV block after messing with drugs from different families but same effect (pharmacodynamics)? Three. And remember that drugs are like drinks when you go to a bar: don't mix!

He already takes two AV node brakers and you add a third, and are you surprised that he gets complete AV block after messing with drugs from different families but same effect (pharmacodynamics)? [HIDDEN] And remember that drugs are like drinks when you go to a bar: don't mix!

An 82-year-old hypertensive woman on atenolol, hydrochlorothiazide and digoxin. She comes to the emergency room for atrial fibrillation and is administered IV verapamil. The ECG showed complete atrioventricular block. What is the most probable cause of this clinical situation?

Digitalis intoxication due to pharmacokinetic interaction with verapamil.

Hypokalemia due to administration of thiazide and digoxin.

Pharmacodynamic interaction of beta-blocker, digoxin and verapamil.

Hypotensive effect of thiazide diuretic.

Digoxin

Digoxin can lead to cardiac arrhythmias when given with thiazides and loop diuretics. This is because co-administration of Digoxin with drugs such as thiazides and loop diuretics which can cause hypokalemia, low serum levels of potassium in the blood. This exacerbates the potential for cardiac arrythmias because the low levels of potassium reduces the amount of K+ at the ATPase pump and increase calcium levels too much which leads to these arrythmias. It can also cause visual disturbances as well as dizziness or fainting. Several other drugs associated with ADRs in concommitant use include verapamil, amiodarone, quinidine, tetracycline, and erythromycin.

[Unwanted drug interaction between anti-arrhythmic drugs and drugs used for heart failure].

The appearance of adverse drug reactions may depend on the category of used drugs as well as on the coexistence of a pathological stage. Clinically important are: interactions of digitalis glycoside drugs leading to the occurrence or intensification of toxic symptoms characteristic for those drugs; interactions of antiarrhythmic drugs which may cause proarrhythmic effects and hypotension, and also interactions of nitrates resulting in lowering of the blood pressure. Quinidine, verapamil, nitrendipine, amiodaron, propafenone, captopril, spironolactone decrease renal clearance of digoxin, and amilorid/triamteren lower the extrarenal clearance of this drug. Thus the outcome of those concommitant therapies is the increase of digoxin serum concentration and appearance of toxic symptoms. Clinically dangerous, in the course of the antiarrhythmic therapy, is the increased risk of the arrhythmia appearance when two or more antiarrhythmic drugs are applied concomitantly. Antiarrhythmic drugs class IA (quinidine, disopyramide), class III (sotalol, amiodarone), class IV (calcium channel blockers) used at the same time with potassium depleters diuretics or beta-blocking agents result in the inhibition of repolarization and the increased duration of activation potential with the risk of developing arrhythmia of the torsade de pointes types. Nitrates interactions are mainly of the pharmacodynamic character. Most common adverse drug reaction, observed during the concomitant nitrates and another circulatory drug therapy, is excessive lowering of the blood pressure. These may lead to the decrease in the therapeutic efficacy of these combinations. Interactions of circulatory drugs are numerous, sometimes difficult to predict and they may lead to the intensification of the adverse drug reaction and lowering of their therapeutic efficacy.

An autopsy case of combined drug intoxication involving verapamil, metoprolol and digoxin.

We present here a fatal poisoning case involving verapamil, metoprolol and digoxin. A 39-year-old male was found dead in his room, and a lot of empty packets of prescribed drugs were found near the corpse. The blood concentrations of verapamil, metoprolol and digoxin were 9.2 microg/ml, 3.6 microg/ml and 3.2 ng/ml, respectively. The cause of death was given as cardiac failure, hypotension and bradycardia due to a mixed drug overdose of verapamil, metoprolol and digoxin, based on the results of the autopsy and toxicological examination. We speculate that the toxicity of verapamil is potentiated by drug interaction with metoprolol and digoxin.

Calcium channel antagonists. Part IV: Side effects and contraindications drug interactions and combinations.

With the correct selection of drug and patient, the calcium antagonists as a group can be remarkably effective at relatively low cost of serious side effects. Almost all side effects are dose related. Minor side effects include those caused by vasodilation (flushing and headaches), constipation (verapamil), and ankle edema. Serious side effects are rare and result from improper use of these agents, as when intravenous verapamil (or diltiazem) is given to patients with sinus or atrioventricular nodal depression from drugs or disease, or nifedipine to patients with aortic stenosis. The potential of a marked negative inotropic effect is usually offset by afterload reduction, especially in the case of nifedipine which actually has the most marked negative inotropic effect. Yet caution is required when even calcium antagonists, especially verapamil, are given to patients with myocardial failure unless caused by hypertensive heart disease. Drug interactions of calcium antagonists occur with other cardiovascular agents such as alpha-adrenergic blockers, beta-adrenergic blockers, digoxin, quinidine, and disopyramide. The most marked interaction with digoxin is that with verapamil, which may raise digoxin levels by over 50%. Combination therapy of calcium antagonists with beta-blockers is increasingly common, and is probably safest in the case of dihydropyridines. Other combinations being explored are those with angiotensin-converting enzyme inhibitors and diuretics.

Verapamil and digoxin: interactions in the rat.

Verapamil and digoxin are often used in combination and clinical experience suggests that verapamil may increase digoxin toxicity. We have explored the effects of verapamil upon digoxin induced tachyarrhythmias and have undertaken a preliminary study of the influence of verapamil on digoxin pharmacokinetics in the rat. Anesthetized rats received 20 mg/kg of digoxin intraperitoneally followed by verapamil i.v., 0.3 mg/kg, in repeated doses either immediately after digoxin or only after the onset of digoxin induced arrhythmias. Digoxin alone produced prolonged paroxysmal atrial tachycardia in 88-100% of rats and verapamil converted 75% of rats to sinus rhythm and significantly reduced digoxin induced mortality. In a later study, rats were injected with 10 mg/kg verapamil i.p. twice a day for 7 days or only with saline. On the seventh day all the rats received 0.5 mg/kg of digoxin i.p. Eight hours later the animals were sacrificed and plasma, heart, brain, liver, kidney and muscle (diaphragm) digoxin concentration was measured by radioimmunoassay. Digoxin levels were twice as high in plasma, heart, liver and muscle of verapamil pretreated rats (p less than 0.01). Two types of verapamil - digoxin interactions are demonstrated in the above studies; one in which verapamil modifies digoxin induced arrhythmias and a second pharmacokinetic effect in which pretreatment with verapamil increases digoxin concentration in the plasma and in several tissues.

Verapamil

Verapamil was approved for medical use in the United States in 1981. It is on the World Health Organization's List of Essential Medicines. Verapamil is available as a generic medication. Long acting formulations exist. In 2019, it was the 141st most commonly prescribed medication in the United States, with more than 4million prescriptions. Medical uses Verapamil is used for controlling ventricular rate in supraventricular tachycardia and migraine headache prevention. It is a class-IV antiarrhythmic and more effective than digoxin in controlling ventricular rate. Verapamil is not listed as a first line agent by the guidelines provided by JAMA in JNC-8. However, it may be used to treat hypertension if patient has co-morbid atrial fibrillation or other types of arrhythmia.

Effectiveness of verapamil-quinidine versus digoxin-quinidine in the emergency department treatment of paroxysmal atrial fibrillation.

To determine the relative effectiveness of a verapamil-quinidine sequential combination versus digoxin-quinidine in the emergency department treatment of paroxysmal atrial fibrillation (PAF). This prospective, double-blind, randomized, controlled trial involved patients, aged 18 to 75 years, with new-onset (< 48 hours) atrial fibrillation who presented to a community-based urban hospital with an annual ED census of 65,000. Exclusion criteria included ventricular response rate lower than 100 or higher than 200 beats/minute, allergy to study drugs, hypotension with evidence of end-organ hypoperfusion, and conduction abnormalities. Consenting patients were randomly assigned to receive rapid digitalization (1.0 mg over 2 hours) or i.v. verapamil (sequential 5-mg boluses up to 20 mg). After ventricular rate was controlled (< 100 beats/minute), oral quinidine (200 mg) was initiated and repeated every 2 hours until conversion to normal sinus rhythm (NSR) occurred, until 1 g of quinidine was administered, or until adverse effects supervened. Heart rate, blood pressure, cardiac rhythm, time to conversion, and adverse effects were documented. Forty-four patients received the study drugs. Three were withdrawn, leaving 19 in the verapamil-quinidine (VER-Q) group and 22 in the digoxin-quinidine (DIG-Q) group. Sixteen patients (84%) in the VER-Q group and 10 (45%) in the DIG-Q group converted to NSR within 6 hours (P < .02). Mean time to conversion (+/-SD) was 185 +/- 146 minutes for VER-Q and 368 +/- 386 minutes for DIG-Q patients (P = NS). Twelve VER-Q patients (63%) and 6 DIG-Q patients (27%) were discharged from the ED (P < .05). Minor adverse effects were more common in the VER-Q group. No mortality or significant morbidity occurred. The sequential combination of verapamil and quinidine, in the doses studied, is an effective treatment for PAF and is superior to digoxin-quinidine. Digoxin should no longer be considered the treatment of choice for uncomplicated PAF.

Identification of severe potential drug-drug interactions using an Italian general-practitioner database.

To analyze prescriptions in a general-practitioner database over 1 year to determine the frequency, the characteristics, and the monitoring of the severe potential drug-drug interactions (DDIs). We retrospectively analyzed the clinical records from 16 general practitioners in the Veneto region, an area in northern Italy. The study covered the period from January 1 to December 31, 2004. We selected all severe and well-documented interactions according to the book Drug Interaction Facts by David S. Tatro (Facts and Comparisons, St. Louis, MO, 2006). We grouped severe potential DDIs according to their specific potential risk, and for the most frequently interacting drug pairs, we investigated whether some specific tests had been prescribed by physicians for safety monitoring. During the study period, 16,037 patients (55% female) with at least one drug prescription were recorded, and a total of 185,704 prescriptions relating to 1,020 different drugs were analyzed. Ramipril was the most frequently prescribed drug followed by acetylsalicylic acid and atorvastatin. The final number of different types of severe potential DDIs was 119, which occurred 1,037 times in 758 patients (4.7% of the total number of patients). More than 80% of drugs involved in severe potential DDIs were cardiovascular drugs. Digoxin was the most frequently involved drug. Electrolyte disturbances, increase in serum digoxin levels, risk of hemorrhage, severe myopathy or rhabdomyolysis, and cardiac arrhythmias were the most commonly implicated potential risks. When considering patients using digoxin with loop or thiazide diuretics for more than 5 months, 72% had at least one test to monitor potential digoxin toxicity, whereas 28% had no tests. Sixty-four percent of patients using digoxin with amiodarone, verapamil, or propafenone had an ECG and/or digoxin monitoring, and 36% of them did not have any tests. The present study revealed that, in a group of Italian general practitioners, the risks of severe potential drug interactions are relatively low and the drugs concerned are few. Analyses of specific tests showed that physicians are generally aware of the potential risks caused by digoxin drug associations. However not all patients were closely monitored and this should be improved.

Management of atrial fibrillation

Rate control Rate control is achieved with medications that work by increasing the degree of block at the level of the AV node, effectively decreasing the number of impulses that conduct down into the ventricles. This can be done with: Beta blockers (preferably the "cardioselective" beta blockers such as metoprolol, bisoprolol, atenolol) Calcium channel blockers (i.e. diltiazem or verapamil) Cardiac glycosides (i.e. digoxin) – have limited use, apart from in the sedentary elderly patient In addition to these agents, amiodarone has some AV node blocking effects (particularly when administered intravenously), and can be used in individuals when other agents are contraindicated or ineffective (particularly due to hypotension). Diltiazem has been shown to be more effective than either digoxin or amiodarone. Drugs used to control the rate of AF may cause side effects, especially fatigue and dyspnea. These are avoided by the more radical "ablate and pace" treatment (see below).

Verapamil-digoxin interaction in chronic hemodialysis patients.

Verapamil increases the serum-digoxin concentration (SDC) in digoxin treated normals due to a compromised renal and extrarenal clearance. In chronic hemodialysis patients (CHD-patients) treated with digoxin where the renal elimination is diminished, verapamil has been shown to cause substantial increases of SDC with risk of digoxin intoxication. The effect of verapamil treatment on SDC in 8 nearly anephric (Uvol less than 1 l/d) CHD-patients on digoxin treatment was assessed. The patients were continuously treated with verapamil for two periods of two weeks at two dosage levels, 120 mg/d and 240 mg/d, whereafter verapamil was withdrawn. SDC and serum-verapamil were measured weekly. The SDC increased from 1.1 mmol/l to 1.7 mmol/l (p less than 0.05, N = 7) during the first two weeks. Increasing the dose of verapamil to 240 mg/d did not cause a further increment in SDC; on the contrary, the mean SDC decreased. The SDC increments varied between 0 and 200% of baseline values. We conclude that verapamil treatment decreases digoxin clearance in CHD-patients and that the influence of verapamil on SDC in CHD-patients shows great interindividual variation with no close dose dependency and decreases to pretreatment level in 2-3 weeks.

The comparative effects of verapamil and a new dihydropyridine calcium channel blocker on digoxin pharmacokinetics.

Conflicting conclusions have been reported about interaction of calcium channel blockers with digoxin. The effects of verapamil (240 mg/day) and a new dihydropyridine calcium channel blocker, isradipine (15 mg/day), on the pharmacokinetics of 1 mg intravenous digoxin were compared. All 24 volunteer subjects were healthy, male, nonobese, and aged 18 to 38 years. Groups of 12 subjects received each oral agent over 15 days, with collections of blood and urine for 72 hours after intravenous digoxin. Significant (P less than 0.05) reduction in nonrenal (7.01 +/- 1.97 to 4.00 +/- 1.86 L/hr) and total clearance (14.1 +/- 2.6 to 11.5 +/- 2.5 L/hr) were induced by verapamil, without change in renal clearance. A near-significant (P less than 0.1) increase in peripheral volume of distribution contributed to prolonged elimination half-life (23.1 +/- 4.4 to 34.3 +/- 9.7 hours). By contrast, isradipine caused only a 9% reduction in volume of distribution. Verapamil causes digoxin accumulation by reducing nonrenal elimination. No evidence of clinically relevant interaction of isradipine with digoxin was seen.

Effects of verapamil on pharmacokinetics and pharmacodynamics of digitoxin in patients.

Investigations by various teams have shown that combined treatment with verapamil and digoxin may result in a marked increase in digoxin plasma concentrations, necessitating a reduction in the dose of digoxin. This is mainly due to an impairment of the renal digoxin excretion. Unlike digoxin, the excretion of digitoxin is independent of renal function. A prospective clinical study was therefore planned to investigate the influence of a daily dose of 240 mg of verapamil on pharmacokinetics and the cardiac effect of digitoxin after a single dose (n = 3) and under steady-state conditions (n = 10). While pretreatment with verapamil did not alter pharmacokinetics of digitoxin in the single-dose study, there was a slight rise of digitoxin plasma concentrations (an average of 35% in 8 out of 10 patients) following administration of verapamil for a period of 4 to 6 weeks. Renal excretion of digitoxin, however, was not changed significantly. Simultaneous with a rise of digitoxin plasma concentrations and until a new steady state was reached, PQ interval was prolonged and T wave flattening intensified. On the other hand, the antagonistic effect on contractility which was initially observed after verapamil administration was diminished. Based on these observations, it can be concluded that the risk of digitalis overdose after combined treatment with verapamil and digitoxin may be less pronounced than after digoxin, and that this glycoside can prove a valuable alternative.

Current concepts in the use of digitalis.

After more than two centuries of administration of digitalis glycosides to patients with cardiac disease, empirical observation and tradition remain the basis for much of the clinical application of these drugs. Many questions remain, and the role of digitalis in the management of congestive heart failure and cardiac rhythm disturbances is changing with improvement in our understanding of the pathophysiology of these conditions and the availability of newer effective agents that may have less potential to cause life-threatening toxicity. Nevertheless, digitalis glycoside therapy is a familiar therapeutic intervention for the majority of physicians and remains appropriate in carefully selected patients. The development of digoxin-specific Fab fragments has led to improvement in treatment of advanced and refractory digitalis toxicity and opens up the possibility of improvement in diagnosis of less clinically obvious cases of digitalis intoxication. The role of digitalis glycosides in the management of supraventricular tachyarrhythmias and congestive heart failure in the presence of sinus rhythm should now be revised. In each of these clinical circumstances, alternative drugs or other modes of therapy have been developed that reduce the dependence of clinicians on digitalis as the sole or primary approach to management. In the immediate management of paroxysmal reentrant supraventricular tachyarrhythmias, verapamil has largely replaced digoxin as the drug of choice, although digoxin has an ancillary role, especially in patients with impaired ventricular function. In the management of patients with atrial fibrillation or atrial flutter with a rapid ventricular response, verapamil or diltiazem and beta-adrenergic-blocking drugs will effectively slow the ventricular response, thus reducing the likelihood of approaching the threshold of digitalis toxicity to achieve adequate rate control. In the treatment of patients with congestive heart failure and normal sinus rhythm, one must now recognize a subset of patients with diastolic rather than systolic dysfunction who are best treated by correcting underlying causes of left ventricular hypertrophy or ischemia rather than inotropic support with cardiac glycosides. Symptomatic patients with dilated ventricles and impaired contractile function should undergo correction of abnormalities of preload with vasodilators acting on the venous bed as well as diuretics, and reduction of elevated afterload with vasodilators that reduce arteriolar resistance and thus improve ventricular emptying.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacology_Katzung

In patients with relatively low blood pressure, dihydropyridines can cause further deleterious lowering of pressure. Verapamil and diltiazem appear to produce less hypotension and may be better tolerated in these circumstances. In patients with a history of atrial tachycardia, flutter, and fibrillation, verapamil and diltiazem provide a distinct advantage because of their antiarrhythmic effects. In the patient receiving digitalis, verapamil should be used with caution, because it may increase digoxin blood levels through a pharmacokinetic interaction. Although increases in digoxin blood level have also been demonstrated with diltiazem and nifedipine, such interactions are less consistent than with verapamil.

Digoxin-verapamil interaction: reduction of biliary but not renal digoxin clearance in humans.

The interaction between digoxin and verapamil was studied in six patients (mean age +/- SD, 61 +/- 5 years) with chronic atrial fibrillation. The effects of adding verapamil (240 mg/day) on steady-state plasma concentrations and renal and biliary clearances of digoxin were studied in a crossover manner. The biliary clearance of digoxin was determined by a duodenal perfusion technique. Verapamil induced a 44% increase in steady-state plasma concentrations of digoxin, from 0.80 +/- 0.24 to 1.15 +/- 0.40 nmol/L (p less than 0.01). The biliary clearance of digoxin decreased by 43%, from 187 +/- 89 to 101 +/- 55 ml/min (p less than 0.05), in the presence of verapamil, whereas the renal clearance was unaffected (153 +/- 31 versus 173 +/- 51 ml/min; difference not significant). Our results indicate that the main inhibitory effect of verapamil on digoxin elimination is on the biliary route.

P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil.

Digoxin, which has a very narrow therapeutic window, is one of the most commonly prescribed drugs in the treatment of congestive heart failure. In some cases of atrial fibrillation digoxin is used in combination with verapamil. Verapamil can increase the plasma concentration of digoxin up to 60-90%. So far the precise mechanism of this pharmacokinetic drug-drug interaction is not known. Many studies suggest that verapamil reduces the renal clearance of digoxin. The energy-dependent membrane-bound transport enzyme, P-glycoprotein, may also be involved. Reports from oncology research show that verapamil can interact with P-glycoprotein as a modulator. Also taking into account that digoxin, like many anticancer drugs, is a substrate for P-glycoprotein, it is likely that P-glycoprotein modulation accounts for the digoxin-verapamil interaction. Current knowledge suggest that the non-competitive digoxin-verapamil interaction is due to inhibition of P-glycoprotein activity by verapamil resulting in a decreased renal tubular elimination of digoxin.

Therapeutic Uses of Diuretic Agents -- Contraindications -- Drug-interactions

Diuretic-induced hypokalemia can increase the risk of digitalis-induced arrhythmia. [163] Digoxin competes with K+ ions for its binding site on the Na+-K+-ATPase pump in the heart, and thus in diuretic-induced hypokalemia, the action of digoxin is unopposed, leading to fatal arrhythmias. [171] Although any diuretic causing hypokalemia can lead to this effect, loop diuretics carry the greatest risk when compared to other classes of diuretics, but as an individual agent, hydrochlorothiazide had the greatest risk. [172] Hence the combination of hypokalemia-inducible diuretics and digoxin can be dangerous and must be avoided. Similarly, clinicians must avoid using quinidine because thiazide-induced hypokalemia can potentiate its cardiovascular effects. [173]

List of cardiac pharmaceutical agents

Antiarrhythmic agents Type I (sodium channel blockers) Type Ia Ajmaline Procainamide Quinidine Type Ib Lidocaine Phenytoin Type Ic Encainide Flecainide Propafenone Type II (beta blockers) Bisoprolol Carvedilol Metoprolol Propranolol Type III (potassium channel blockers) Amiodarone Dofetilide Sotalol Type IV (slow calcium channel blockers) Diltiazem Verapamil Type V Adenosine Digoxin ACE inhibitors Captopril Enalapril Perindopril Ramipril Angiotensin II receptor antagonists Candesartan Eprosartan Irbesartan Losartan Telmisartan Valsartan Beta blocker (see above) Calcium channel blocker (see above) Antimineralocorticoid Eplerenone Finerenone Spironolactone Antiplatelet drug Abciximab Aspirin Cangrelor Clopidogrel Eptifibatide Prasugrel Ticagrelor Tirofiban Anticoagulant Apixaban Bivalirudin Dabigatran Edoxaban Enoxaparin Heparin Rivaroxaban Warfarin Fibrinolytics Alteplase Streptokinase Urokinase Diuretics

Long-term oral treatment with high doses of verapamil in lone atrial fibrillation.

It has earlier been shown that verapamil given intravenously or orally in sufficiently high single doses, may result in regular ventricular rhythm in patients with atrial fibrillation. We have analyzed whether this effect of verapamil can be utilized in long-term oral treatment. Eleven patients with lone atrial fibrillation were studied. Verapamil was given in gradually increasing doses from 40 mg three times a day to 320 mg three times a day, either alone or in combination with digoxin. Resting ECG was recorded and supine and standing blood pressures were measured on each dose level. When the patients were treated with verapamil alone, only a slight decrease in heart rate was noted, while during combined treatment with verapamil and digoxin a more marked heart rate decrease occurred with increasing doses of verapamil. The variation coefficient of the RR interval, a sign of ventricular regularity, decreased during verapamil treatment regardless of whether or not digoxin was also taken. A dose-dependent blood pressure decrease was noted during verapamil treatment. Side effects were common and led to discontinuation of the attempted protocol in all patients. Three patients were unexpectedly converted to stable sinus rhythm. Five patients improved subjectively, with a marked decrease in the sensation of palpitations during intake of increasing doses of verapamil. The study indicates that chronic oral treatment with verapamil may sometimes relieve the subjective sensation of palpitations in patients with atrial fibrillation. Side effects do, however limit the value of this mode of treatment in the majority of patients.

Proarrhythmia

Atrial proarrhythmia Conversion of atrial fibrillation to flutter (usually VW type IC drugs or amiodarone). May be a desired effect. Increase of defibrillation threshold (a potential problem with VW type IC drugs) Provocation of recurrence (probably VW types IA, IC and III drugs). It is rare. Abnormalities of conduction or impulse formation Sinus node dysfunction, atrioventricular block (almost all drugs) Accelerate conduction over accessory pathway (digoxin, intravenous verapamil, or diltiazem) Acceleration of ventricular rate during atrial fibrillation (VW type IA and type IC drugs). Increased risk Presence of structural heart disease, especially LV systolic dysfunction. Class IC agents. Increased age. Females. Clinical pointers Class IA drugs Dose independent, occurring at normal levels. Follow QT interval, keep ms. Class IC drugs May be provoked by increased heart rate. Exercise stress tests after loading.

Influence of verapamil on the digoxin-induced inotropic effect in guinea-pig isolated atria.

The nature of the digoxin-verapamil interaction was explored "in vitro" by determining the effect of verapamil on digoxin-induced inotropism in isolated guinea-pig atria. Verapamil, at concentrations (2.10(-8)-3.10(-8)M) too low to have any significant effect on the amplitude or frequency of the basal contractile activity, reduced the inotropic action of digoxin in all experimental circumstances, i.e. in spontaneously beating atria from reserpine-treated or untreated animals, in electrically driven (at 1 Hz frequency stimulation) left atria. The results obtained suggest that a competitive antagonism exists between verapamil and digoxin. In spontaneously beating atria an apparently competitive antagonism was also observed between verapamil and ouabain. The interaction observed between cardiac glycosides and the Ca++ channel blocker suggests that Ca++ movements across the sarcolemma may influence the inotropic effect of digitalis or its toxicity.

WHO Model List of Essential Medicines

Antianginal medicines Bisoprolol Glyceryl trinitrate Isosorbide dinitrate Verapamil Antiarrhythmic medicines Bisoprolol Digoxin Epinephrine (adrenaline) Lidocaine Verapamil Amiodaroneα Antihypertensive medicines Amlodipine Bisoprolol Enalapril Hydralazine Hydrochlorothiazide Lisinopril/amlodipine (lisinopril + amlodipine) Lisinopril/hydrochlorothiazide (lisinopril + hydrochlorothiazide) Losartan Methyldopa Telmisartan/amlodipine (telmisartan + amlodipine) Telmisartan/hydrochlorothiazide (telmisartan + hydrochlorothiazide) Sodium nitroprussideα Medicines used in heart failure Bisoprolol Digoxin Enalapril Furosemide Hydrochlorothiazide Losartan Spironolactone Dopamineα Antithrombotic medicines Anti-platelet medicines Acetylsalicylic acid (aspirin) Clopidogrel Thrombolytic medicines Alteplaseα Streptokinaseα Lipid-lowering agents Simvastatin Dermatological medicines (topical)

Atrial fibrillation

Rate control Rate control to a target heart rate of fewer than 110 beats per minute is recommended in most people. Lower heart rates may be recommended in those with left ventricular hypertrophy or reduced left ventricular function. Rate control is achieved with medications that work by increasing the degree of the block at the level of the AV node, decreasing the number of impulses that conduct into the ventricles. This can be done with: Beta blockers (preferably the "cardioselective" beta blockers such as metoprolol, bisoprolol, or nebivolol) Non-dihydropyridine calcium channel blockers (e.g., diltiazem or verapamil) Cardiac glycosides (e.g., digoxin) – have less use, apart from in older people who are sedentary. They are not as effective as either beta-blockers or calcium channel blockers. In those with chronic AF either beta blockers or calcium channel blockers are recommended.

List of side effects of digoxin

Side effects due to other drug interactions Side effects can become more pronounced due to the drug interactions between digoxin and the following: Thiazide and loop diuretics, piperacillin, ticarcillin, amphotericin B, corticosteroids, and excessive laxative use. Amiodarone, some benzodiazepines, cyclosporine, diphenoxylate, indomethacin, itraconazole, propafenone, quinidine, quinine, spironolactone, and verapamil may lead to toxic levels and increased incidence of side effects. Digoxin plasma concentrations may increase while on antimalarial medication hydroxychloroquine. Patients taking digoxin should avoid taking hawthorn. Side effects due to dietary supplements Side effects can become pronounced due to the interactions of digoxin and these substances: licorice, aloe, and St. John's wort.

Comparative effects of verapamil and isradipine on steady-state digoxin kinetics.

The effects on the steady-state digoxin pharmacokinetics of verapamil (240 mg/day) and a new dihydropyridine calcium channel blocker, isradipine (15 mg/day), were compared. Nineteen healthy white men, aged 23 to 40 years, ingested 0.25 mg digoxin tablets every 12 hours for two consecutive periods of 2 weeks. Each subject also received one of the calcium channel blockers during one of these periods, with agent and sequence randomized. Analyst-blind RIA serum digoxin determinations demonstrated that the nine subjects who received isradipine, 5 mg t.i.d., had a small increment in peak digoxin level from 2.3 +/- 0.6 to 2.9 +/- 0.7 ng/ml (p less than 0.05) but no significant change in steady-state level or AUC over 12 hours. By contrast, the 10 subjects who received verapamil, 80 mg t.i.d., showed significant increases in steady-state (0.9 +/- 0.1 to 1.3 +/- 0.2 ng/ml; p less than 0.001) and peak serum digoxin concentrations (2.5 +/- 0.7 to 3.6 +/- 0.8 ng/ml; p less than 0.001) and in AUC (15.7 +/- 1.7 to 23.6 +/- 2.9 ng . hr/ml; p less than 0.001). Neither calcium channel blocker reduced renal digoxin clearance. Verapamil increases digoxin levels without affecting renal clearance. Isradipine has no clinically important interaction with digoxin.

Digoxin

Several other drugs associated with ADRs in concommitant use include verapamil, amiodarone, quinidine, tetracycline, and erythromycin. Overdose In overdose, the usual supportive measures are needed. If arrhythmias prove troublesome, or malignant hyperkalemia occurs (inexorably rising potassium level due to paralysis of the cell membrane-bound, ATPase-dependent Na/K pumps), the specific antidote is antidigoxin (antibody fragments against digoxin, trade names Digibind and Digifab). The mechanism of action for drugs such as Digibind and Digifab, used when adverse events occur with the use of digoxin, is that the FAB regions on the antibodies created against digoxin expedite the excretion of the drug into urine. Therefore, the amount of Digoxin in the body decreases quickly as it gets excreted rapidly. Pharmacology Pharmacodynamics

Sodium channel blocker

Indications for Class Ia agents are supraventricular tachycardia, ventricular tachycardia, symptomatic ventricular premature beats, and prevention of ventricular fibrillation. Procainamide can be used to treat atrial fibrillation in the setting of Wolff-Parkinson-White syndrome, and to treat wide complex hemodynamically stable tachycardias. Oral procainamide is no longer being manufactured in the US, but intravenous formulations are still available. While procainamide and quinidine may be used in the conversion of atrial fibrillation to normal sinus rhythm, they should only be used in conjunction with an AV node blocking agent such as digoxin or verapamil, or a beta blocker), because procainamide and quinidine can increase the conduction through the AV node and may cause 1:1 conduction of atrial fibrillation, causing an increase in the ventricular rate. Class Ia agents include quinidine, procainamide and disopyramide. Class Ib agents

Amiloride

Amiloride may be used in combination with a thiazide diuretic for treatment of high blood pressure or (less commonly) in combination with a loop diuretic for treatment of heart failure. The potassium-sparing effects of amiloride offset the low blood potassium (hypokalemia) that is often induced by thiazides or loop diuretics, which is of particular importance in people for whom maintaining a normal level of potassium is critically important. For example, people that are taking Digitalis (i.e. digoxin) are at higher risk for changes in heart rhythm if their potassium levels get too high. The 2017 clinical practice guidelines of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines list amiloride as a "secondary" oral antihypertensive, with minimal efficacy. For people with resistant hypertension, already taking a thiazide diuretic, an angiotensin converting enzyme inhibitor (ACE-i) or an angiotensin II receptor blocker (ARB), and a

Verapamil versus digoxin and acute versus routine serial cardioversion for the improvement of rhythm control for persistent atrial fibrillation.

The VERDICT (Verapamil Versus Digoxin and Acute Versus Routine Serial Cardioversion Trial) is a prospective, randomized study to investigate whether: 1) acutely repeated serial electrical cardioversions (ECVs) after a relapse of atrial fibrillation (AF); and 2) prevention of intracellular calcium overload by verapamil, decrease intractability of AF. Rhythm control is desirable in patients suffering from symptomatic AF. A total of 144 patients with persistent AF were included. Seventy-four (51%) patients were randomized to the acute (within 24 h) and 70 (49%) patients to the routine serial ECVs, and 74 (51%) patients to verapamil and 70 (49%) patients to digoxin for rate control before ECV and continued during follow-up (2 x 2 factorial design). Class III antiarrhythmic drugs were used after a relapse of AF. Follow-up was 18 months. At baseline, there were no significant differences between the groups, except for beta-blocker use in the verapamil versus digoxin group (38% vs. 60%, respectively, p = 0.01). At follow-up, no difference in the occurrence of permanent AF between the acute and the routine cardioversion groups was observed (32% [95% confidence intervals (CI)] 22 to 44) vs. 31% [95% CI 21 to 44], respectively, p = NS), and also no difference between the verapamil- and the digoxin-randomized patients (28% [95% CI 19 to 40] vs. 36% [95% CI 25 to 48] respectively, p = NS). Multivariate Cox regression analysis revealed that lone digoxin use was the only significant predictor of failure of rhythm control treatment (hazard ratio 2.2 [95% CI 1.1 to 4.4], p = 0.02). An acute serial cardioversion strategy does not improve long-term rhythm control in comparison with a routine serial cardioversion strategy. Furthermore, verapamil has no beneficial effect in a serial cardioversion strategy.

Outline of cardiology

Ion channels Ion channels are responsible for cell membrane voltage, depolarization, and repolarization. These actions lead to conduction of signals down nerves and contraction of cardiomyocytes. Perhaps the most prominent manipulation of ion channels is through antiarrhythmic agents. These agents are commonly classified by the type of ion they manipulate and named the Vaughan Williams classification: Class I — Sodium channel blockers Class Ia — Fast sodium channels (quinidine, ajmaline, procainamide, disopyramide) Class Ib — Sodium channels (lidocaine, phenytoin, mexiletine, tocainide) Class Ic — Decrease conductivity (encainide, flecainide, propafenone, moricizine) Class II — Beta blockers (carvedilol, propranolol, esmolol, timolol, metoprolol, atenolol, bisoprolol) Class III — Potassium channel blockers (amiodarone, sotalol, ibutilide, dofetilide, dronedarone) Class IV — Calcium channel blockers (verapamil, diltiazem) Class V — Other (adenosine, digoxin, magnesium Sulfate)

Antiarrhythmic Medications -- Monitoring

During the administration of beta-blockers, an electrocardiogram and heart rate monitoring are more useful than TDM. [52] Amiodarone is an excellent antiarrhythmic agent, but long-term use correlates with corneal opacities, thyroid problems, and lung infiltrates. Consequently, amiodarone is not the preferred geriatric population rather than young adults. Digoxin has a narrow therapeutic index. The therapeutic serum digoxin levels range is 0.5 to 2 ng/mL. Serum concentrations of cardiac glycosides require monitoring closely to avoid digitalis toxicity. Amiodarone, verapamil, quinidine, and diltiazem increase the serum levels of digoxin and can lead to toxicity. The recommendation is to reduce the digoxin dose by 25% to 50%, closely monitoring digoxin levels weekly for several weeks. Periodic electrolyte evaluation is a recommendation. Hypokalemia may make the patient more susceptible to digitalis toxicity. Healthcare professionals can reduce the morbidity of antiarrhythmic drugs with knowledge of the adverse drug reactions,pro-arrhythmic effects of specific antiarrhythmic drugs, and therapeutic drug monitoring. [53] [54]

A comparison of verapamil and digoxin for heart rate control in atrial fibrillation.

Atrial fibrillation (AF) is one of the most common types of sustained dysrhythmia and there are some disagreements about its treatment. The goals of AF treatment include the control of ventricular rate, the establishment of sinus rhythm and the prevention of thromboembolic events. In this study, the effect of verapamil was compared to digoxin on heart rate control in patients with AF. This descriptive study was conducted in an emergency department (ED) in Iran. Sixty patients with a new onset AF and rapid ventricular response receiving digoxin or verapamil were included and observed. Two thirty-patient groups receiving verapamil or digoxin were evaluated. The heart rate was significantly decreased in both groups (p = 0.002); however, the cardioversion was not noticed in both of them. The best rate control in verapamil and digoxin groups was observed after 5.9 mg (46.7%) and 0.6 mg (36.7%), respectively. Administration of verapamil in comparison with digoxin has no difference to control the heart rate in AF patients. It should be taken into consideration that prospective randomized studies should be conducted to identify the efficacy and select the best of these two drugs to treat AF patients.