In a polytraumatized patient, the first cause of shock is blood loss (hemorrhagic shock). The guidelines to follow should always contemplate the replenishment of blood volume (if possible, with blood products as early as possible) and control of the focus. In this case, given the vital compromise, the need for transfusion is very urgent, so the indication is emergency blood transfusion (O Rh negative).

A 34-year-old male is involved in a traffic accident and is attended at the scene of the accident. The medical personnel observe that he is pale, sweaty, has a thready pulse with a blood pressure of 90/50 mmHg, a heart rate of 127 bpm, a respiratory rate of 28 rpm and an oxygen saturation of 92%. He was infused with 20 ml/kg of crystalloids. During his transfer to the hospital his vital signs improve transiently and then deteriorate on arrival at the hospital. Point out the correct answer:

Type-specific blood transfusion required.

Requires emergency blood transfusion (O Rh negative).

A possible blood transfusion with crossmatching tests should be prepared.

Try again infusion of another 20 ml/kg of crystalloids.

[Emergency incompatible red cell transfusion to a patient whose blood type was suspended from identification].

We report a case of a 59-year-old woman who presented with hypovolemic shock and compensated acidosis (preoperative arterial blood gases: pH 7.3, P(CO2) 31.9 mmHg, Pa(O2) 112.3 mmHg, base excess -9.8, Hb 6.4 g x dl(-1)) due to perforated descending colon, necessitating emergency surgery. Tracheal intubation had been performed preoperatively. Prior to induction of anesthesia, blood pressure was 106/74 mmHg, heart rate 119 beats x min(-1), and Sp(O2) 100% breathing room air. Anesthesia was induced with remifentanil influsion at a rate of 0.05 mg x kg(-1) x min(-1), sevoflurane 1% and rocuronium bromide 30mg, and was maintained with oxygen, air, remifentanil and sevoflurane. For a critical hypovolemia, in accordance to the guidelines for intraoperative critical hemorrhage and the Japanese practical guidelines for blood components therapy, we started to transfuse incompatible red cell (O+) since the identification of blood typing was suspended. The duration of surgery was 104 min, with an intraoperative total bleeding of 125 ml. Four units of total blood transfusion and 3,050 ml of infusion of Ringer's acetate solution were administered. The patient was transferred to ICU with tracheal intubation. No adverse reactions associated with blood type incompatibility were recognized.

[A patient rescued from unexpected intraoperative massive hemorrhage with ABO incompatible blood transfusion].

A 67-year-old man was scheduled for resection of thoracic intramedullary tumor. His blood type was AB. Unexpectedly rapid and massive hemorrhage occurred during the operation. We infused a large amount of crystalloid, colloid, and 5% albumin. But he went into circulatory collapse before we could get type AB red blood cell (RBC) and hemoglobin was reduced to 3.8 g x dl(-1). We decided to transfuse 4 units of ABO incompatible type O RBC. Later, type AB RBC and other blood components became available and the patient recovered. We conclude that transfusion of ABO incompatible blood in patient with critical hemorrhage should be encouraged to save life.

Blood Transfusion -- Preparation -- Obtain Baseline Vital Signs

These include heart rate, temperature, blood pressure, pulse oximeter, and respiratory rate Respiratory sounds and urine output should also be documented Notify the provider if the temperature is more than 100 F

Blood transfusion

In urgent cases where crossmatching cannot be completed, and the risk of dropping hemoglobin outweighs the risk of transfusing uncrossmatched blood, O-negative blood is used, followed by crossmatch as soon as possible. O-negative is also used for children and women of childbearing age. It is preferable for the laboratory to obtain a pre-transfusion sample in these cases so a type and screen can be performed to determine the actual blood group of the patient and to check for alloantibodies. Compatibility of ABO and Rh system for Red Cell (Erythrocyte) Transfusion This chart shows possible matches in blood transfusion between donor and receiver using ABO and Rh system.

Bleeding

Blood loss Hemorrhaging is broken down into four classes by the American College of Surgeons' advanced trauma life support (ATLS). Class I Hemorrhage involves up to 15% of blood volume. There is typically no change in vital signs and fluid resuscitation is not usually necessary. Class II Hemorrhage involves 15-30% of total blood volume. A patient is often tachycardic (rapid heart beat) with a reduction in the difference between the systolic and diastolic blood pressures. The body attempts to compensate with peripheral vasoconstriction. Skin may start to look pale and be cool to the touch. The patient may exhibit slight changes in behavior. Volume resuscitation with crystalloids (Saline solution or Lactated Ringer's solution) is all that is typically required. Blood transfusion is not usually required.

Blood transfusion

Acute hemolytic reactions are defined according to Serious Hazards of Transfusion (SHOT) as "fever and other symptoms/signs of haemolysis within 24 hours of transfusion; confirmed by one or more of the following: a fall of Hb, rise in lactate dehydrogenase (LDH), positive direct antiglobulin test (DAT), positive crossmatch" This is due to destruction of donor red blood cells by preformed recipient antibodies. Most often this occurs because of clerical errors or improper ABO blood typing and crossmatching resulting in a mismatch in ABO blood type between the donor and the recipient. Symptoms include fever, chills, chest pain, back pain, hemorrhage, increased heart rate, shortness of breath, and rapid drop in blood pressure. When suspected, transfusion should be stopped immediately, and blood sent for tests to evaluate for presence of hemolysis. Treatment is supportive. Kidney injury may occur because of the effects of the hemolytic reaction (pigment nephropathy). The severity of the

Hypovolemia

Medical personnel should immediately supply emergency oxygen to increase efficiency of the patient's remaining blood supply. This intervention can be life-saving. The use of intravenous fluids (IVs) may help compensate for lost fluid volume, but IV fluids cannot carry oxygen the way blood does—however, researchers are developing blood substitutes that can. Infusing colloid or crystalloid IV fluids also dilutes clotting factors in the blood, increasing the risk of bleeding. Current best practice allow permissive hypotension in patients suffering from hypovolemic shock, both avoid overly diluting clotting factors and avoid artificially raising blood pressure to a point where it "blows off" clots that have formed. Hospital treatment Fluid replacement is beneficial in hypovolemia of stage 2, and is necessary in stage 3 and 4. See also the discussion of shock and the importance of treating reversible shock while it can still be countered.

InternalMed_Harrison

Same, plus: 1750 to deficient clotting factors in crystalloids and banked packed red blood cells (PRBCs). Early administration of component therapy during massive transfusion (fresh-frozen plasma [FFP] and platelets) approaching a 1:1 ratio of PRBC/FFP appears to improve survival. In extreme emergencies, type-specific or O-negative packed red cells may be transfused. Following severe and/or prolonged hypovolemia, inotropic support with norepinephrine, vasopressin, or dopamine may be required to maintain adequate ventricular performance but only after blood volume has been restored. Increases in peripheral vasoconstriction with inadequate resuscitation lead to tissue loss and organ failure. Once hemorrhage is controlled and the patient has stabilized, blood transfusions should not be continued unless the hemoglobin is <~7 g/dL. Studies have demonstrated an increased survival in patients treated with this restrictive blood transfusion protocol. Successful resuscitation also requires

Masimo

rainbow Pulse CO-Oximetry uses more than seven wavelengths of light to continuously and noninvasively measure hemoglobin (SpHb), carboxyhemoglobin (SpCO), and methemoglobin (SpMet), in addition to oxygen saturation (SpO2), pulse rate, perfusion index (Pi), and pleth variability index (PVi). A study at Massachusetts General Hospital showed that SpHb monitoring helped clinicians decrease the frequency of patients receiving blood transfusions during surgery from 4.5% to 0.6%. Another study from Cairo University showed that SpHb monitoring helped clinicians reduce blood transfusions in high blood loss surgery by an average of 0.9 units per patient. A study at CHU Limoges in France found that monitoring with SpHb and PVi, integrated into a hospital-wide fluid and blood administration protocol, was associated with earlier transfusion and reduced mortality at 30 and 90 days by 33% and 29%, respectively. Emergency department studies have shown that SpCO helps clinicians increase the detection

Damage control surgery

For over a century the casualties of war have provided valuable lessons that can be applied within the civilian sector. Specifically the past decade has seen a paradigm shift in early resuscitation of critically injured patients. Instead of replacing blood volume with high volumes of crystalloid and packed red blood cells with the sporadic use of fresh frozen plasma and platelets, we have now learned that maintaining a transfusion ratio of 1:1:1 of plasma to red blood cells to platelets in patients requiring massive transfusion results in improved outcomes [Borgman 2007] While this was initially demonstrated in the military setting, Holcomb and colleagues extrapolated this to the civilian trauma center showing improved results as well Broad implementation across both the military and civilian sector has demonstrated a decreased mortality in critically injured patients. Debate has gone back and forth as to the correct ratio that should be used; however, recently Holcomb and colleagues

Bleeding

Class III Hemorrhage involves loss of 30-40% of circulating blood volume. The patient's blood pressure drops, the heart rate increases, peripheral hypoperfusion (shock) with diminished capillary refill occurs, and the mental status worsens. Fluid resuscitation with crystalloid and blood transfusion are usually necessary. Class IV Hemorrhage involves loss of >40% of circulating blood volume. The limit of the body's compensation is reached and aggressive resuscitation is required to prevent death.

Sepsis

The Surviving Sepsis Campaign has recommended 30 ml/kg of fluid to be given in adults in the first three hours followed by fluid titration according to blood pressure, urine output, respiratory rate, and oxygen saturation with a target mean arterial pressure (MAP) of 65 mmHg. In children an initial amount of 20 ml/kg is reasonable in shock. In cases of severe sepsis and septic shock where a central venous catheter is used to measure blood pressures dynamically, fluids should be administered until the central venous pressure reaches 8–12 mmHg. Once these goals are met, the central venous oxygen saturation (ScvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized. If the ScvO2 is less than 70%, blood may be given to reach a hemoglobin of 10 g/dL and then inotropes are added until the ScvO2 is optimized. In those with acute respiratory distress syndrome (ARDS) and sufficient tissue blood fluid, more fluids should be given

Pneumonia

Pneumonia can cause severe illness in a number of ways, and pneumonia with evidence of organ dysfunction may require intensive care unit admission for observation and specific treatment. The main impact is on the respiratory and the circulatory system. Respiratory failure not responding to normal oxygen therapy may require heated humidified high-flow therapy delivered through nasal cannulae, non-invasive ventilation, or in severe cases invasive ventilation through an endotracheal tube. Regarding circulatory problems as part of sepsis, evidence of poor blood flow or low blood pressure is initially treated with 30 ml/kg of crystalloid infused intravenously. In situations where fluids alone are ineffective, vasopressor medication may be required.

[Oxygen transport values in patients with surgery performed under extracorporeal blood circulation].

The aim of the work was to study the O2-transport changes to tissues in cardio-surgical patients suffering from CAD and operated during extra-corporeal blood circulation (ECC). The changes of selected haematologic variables, 2,3-diphosphoglycerate (2,3-DPG) and ATP concentration, acid-base balance parameters with p50 calculation were measured in the venous blood samples taken before the operation, during the operation and on the 1st, 2nd, 3d, 5th, 7th and 10th day after the operation. From the obtained results follows, that extreme haemodilution causes significant decrease of the haematocrit value (Htc) by 35%, the value of haemoglobin (Hb) by 37% and the count of erythrocytes (Er) by 37% from the initial values. The count of reticulocytes (Ret) was increased by 52%. In the days after operation the increase in Htc values, the values of Hb and count of erythrocytes was observed, whereby the initial values were not reach even on the 10th day after the operation. The increase of the reticulocytes count by 33% prevailed to the 10th day after the operation in comparison with the initial values. 2,3-DPG concentration was increased between 3d and 10th day after the operation by 30% and ATP concentration between 5th and 10th day was increased by 23% from the initial values. Hb-O2 saturation (SpO2) and pO2 were increased already during the operation, the increase prevailed until the 7th day by 27%, pO2 until the 3d day by 39% from the initial values. Calculated values p50 did not change in the course of this study--they fluctuated in range +/- 0.04 kPa from the initial value 3.55 kPa. Supposing multifactorial character of Hb oxygenation and deoxygenation process it is possible to conclude, that the determined changes of observed parameters did not significantly influence O2-transport to tissues during ECC. (Fig. 3, Ref. 12.)

Shock (circulatory)

Fluids Aggressive intravenous fluids are recommended in most types of shock (e.g. 1–2 liter normal saline bolus over 10 minutes or 20 ml/kg in a child) which is usually instituted as the person is being further evaluated. Colloids and crystalloids appear to be similar with respect to outcomes., Balanced crystalloids and normal saline also appear to be similar in critically ill patients. If the person remains in shock after initial resuscitation, packed red blood cells should be administered to keep the hemoglobin greater than 100 g/l. For those with hemorrhagic shock, the current evidence supports limiting the use of fluids for penetrating thorax and abdominal injuries allowing mild hypotension to persist (known as permissive hypotension). Targets include a mean arterial pressure of 60 mmHg, a systolic blood pressure of 70–90 mmHg, or until their adequate mentation and peripheral pulses. Hypertonic fluid may also be an option in this group. Medications

[Preoperative hemodilution to reduce homologous blood transfusion--effects on hemodynamics and oxygen flux].

Many problems arise from homologous blood transfusion in operative patients. Preoperative collection of blood with hemodilution is a simple method to allow autologous blood transfusion. Sixty patients who received gynecological operations were divided into three groups. Patients in the first and second groups underwent preoperative blood collection and hemodilution, and collected blood was transfused during operation when bleeding volume had exceeded prefixed value. The volume and speed of blood collection were 20 ml.kg-1 and 30 minutes in the first group, and 20 ml.kg-1 and 15 minutes in the second group. After the collection of blood, HES solution was infused to maintain blood volume. The patients in the third group were transfused with homologous blood as controls. The blood pressure, heart rate, cardiac index and oxygen flux were maintained well in the first group after collection of blood and hemodilution. The hemoglobin concentration was kept at 10 g.dl-1 when the operation was terminated with a mean bleeding volume of 1,014 ml. The results suggest that the method of preoperative blood collection and hemodilution followed by autologous blood transfusion is a promising technic to reduce the amount of homologous blood transfusion in operative patients.

Prehospital administration of blood products: experiences from a Finnish physician-staffed helicopter emergency medical service.

Massive infusions of crystalloids into bleeding hypotensive patients can worsen the outcome. Military experience suggests avoiding crystalloids using early damage control resuscitation with blood components in out of hospital setting. Civilian emergency medical services have since followed this idea. We describe our red blood cell protocol in helicopter emergency medical services (HEMS) and initial experience with prehospital blood products from the first 3 years after implementation. We performed an observational study of patients attended by the HEMS unit between 2015 and 2018 to whom packed red blood cells, freeze-dried plasma, or both were transfused. The Student's two-sided T-test was used to compare vitals in prehospital phase with those at the hospital's emergency department. A p-value < 0.05 was considered significant. Altogether, 62 patients received prehospital transfusions. Of those, 48 (77%) were trauma patients and most (n = 39, 81%) suffered blunt trauma. The transfusion began at a median of 33 (IQR 21-47) minutes before hospital arrival. Median systolic blood pressure showed an increase from 90 mmHg (IQR 75-111 mmHg) to 107 mmHg (IQR 80-124 mmHg; P < 0.026) during the prehospital phase. Four units of red blood cells were handled incorrectly when unused red blood cells were returned and required disposal during a three-year period. There were no reported adverse effects from prehospital transfusions. We treated two patients per month with prehospital blood products. A prehospital physician-staffed HEMS unit carrying blood products is a feasible and safe method to start transfusion roughly 30 min before arrival to the hospital. The study was retrospectively registered by the Tampere University Hospital's Medical Director (R19603) 5.11.2019.

Consciously transfusion of blood products. Systematic review of indicative factors for blood components infusion's trigger.

With the surgical and anesthetic technology advance the indications for intervention are expanding, as well as the need for blood transfusions. Because of its great scientific value, the content to be exposed is subject for endless discussions that provide different guidelines in various clinical and laboratory aspects. The objective of this review is to determine the clinical, laboratorial, and monitoring signs that should guide blood transfusion initiation, avoiding any risk and unnecessary use of resources, as well as the delay on starting therapy, determining tissue hypoxia and its corollaries. Scientific articles of clinical trials and reviews were used to range various subjects approached in the present content. These subjects were divided according to clinical and laboratorial aspects. Once the described search finished, 2,608 papers were identified, but only 17 original references were selected by inclusion criteria. Literature is unclear about clinical criteria on the ideal moment to begin the transfusion therapy in order to optimize the relations risk/ and cost/benefit. Studies show that there is no significant difference of oxygen supply (O(2)) in a comparison of hemoglobin (Hb) levels between 6 and 10g.dL(-1), mainly by reduced blood viscosity, facilitating the vascular flow to tissues. However, there is a tendency to recommend the transfusion trigger (TT) when it reaches low values as 6-7g.dL(-1). This same tendency indicates that red blood cells should never be administered with Hb levels > 10g.dL(-1), except in special situations.

Neonatal red cell transfusion

When to transfuse Below are suggested transfusion thresholds for very preterm neonates (less than 32 weeks gestation) by the British Society of Haematology. These are based on systematic reviews of transfusion in very preterm babies. There is no evidence for red cell transfusion thresholds in preterm neonates between 32 and 37 weeks gestation, and the British Society of Haematology suggests using the same thresholds as very preterm neonates that require no respiratory support. What to transfuse A small volume transfusion is usually 10 to 20 ml/kg administered at a rate of 5 ml/kg/hour. A large volume transfusion is the estimated entire blood volume of the baby (80 ml/kg) and is usually given during cardiac surgery.

[Control of the ratio of the flow rate of the substitution fluid to the blood removal rate during preoperative normovolemic hemodilution].

Twenty-one patients (mean age 46 +/- 13 years) due to undergo abdominal or ENT surgery, presumed to give rise to an important blood loss were included in this study. None had any contra-indication to the use of normovolaemic haemodilution (NH). Mean initial haematocrit was 40.3 +/- 1.8%. Their estimated total blood volume was 4,867 +/- 857 ml. The patients were anaesthetized with thiopentone, fentanyl, vecuronium or atracurium. Maintenance was carried out with isoflurane (0.5% during NH). Usual haemodynamic monitoring was used throughout. The required haematocrit was decided on before starting NH. The amount of blood to be removed was calculated with usual mathematical formulae. A radial artery cannula (n = 7), or a subclavian or femoral venous cannula (n = 14) was used to remove blood, which was collected within a bag containing CPC-adenine. Six % hydroxyethyl starch (Elohes) was given through a short venous cannula some distance from the first one. An antiparallel double line set in a roller pump was used to carry out the NH. A mean 1,341 +/- 405 ml of blood were withdrawn so as to reach a mean haematocrit of 30.6 +/- 2.4%. NH was completed within 17 +/- 6 min. No major haemodynamic changes occurred during the procedure. No significant differences were observed between expected and observed final haematocrits. There was no effect of the volume of blood withdrawn on the error of haematocrit prediction (0.5 +/- 0.3%). However, a higher rate of blood removal could increase this error. This easy-to-use device seems to provide fast and identical rates of blood removal and replacement. The expected haematocrit may thus be reached reliably, even if this must be checked for the sake of safety.

Exchange transfusion can be life-saving in severe propanil poisoning: a case report.

Propanil is an important cause of herbicide poisoning in Sri Lanka, accounting for about 2% of all cases of self-poisoning. The outcome is extremely poor when the poisoning is severe and current medical care is of limited efficacy. Death usually occurs due to the severe and prolonged methaemoglobinaemia. We describe a case of severe Propanil poisoning, successfully treated by exchange transfusion at a tertiary care hospital in Sri Lanka. A 17-year old Sri Lankan male (body weight--42 kg), presented to a local hospital 1 hour after self-ingestion of nearly 500 ml (4.3 g/kg) of liquid Propanil (concentration--360 g/l). On admission he had dizziness and peripheral cyanosis. He was given intravenous methylene blue (1 mg/kg) within one hour of admission, which was repeated subsequently due to minimal response. The next day morning, (18 hours after poisoning) the patient was transferred to the National Hospital of Sri Lanka (NHSL) for further management. On admission to NHSL, he was drowsy and confused, had a shallow respiratory effort and marked central and peripheral cyanosis. Respiratory rate was 20/min, with a pulse-oximetry of 77% on room air. The arterial blood gas analysis was as follows; pH--7.24, HCO3(-)--12 mmol/l, pCO2--28 mmHg, pO2--239 mmHg and O2 saturation--100%. Exchange transfusion was commenced within two hours of admission to NHSL. A dramatic improvement in oxygen saturation was observed immediately afterwards, with the saturation in pulse-oximetry rising to >95%. The level of consciousness and respiratory effort also improved. He was discharged subsequently 8 days after the initial poisoning. Propanil has potential to produce severe life threatening clinical manifestations, despite categorization as a herbicide with low toxicity. In cases of severe poisoning, exchange transfusion may be life saving. Since methylene blue, intensive care and exchange transfusion facilities are also not readily available in local hospitals, which frequently encounter cases of severe Propanil poisoning, early transfer of patients to tertiary care hospitals should be considered. Exchange transfusion may be helpful even in late stages in patients with severe poisoning.

[Critical hematocrit from the viewpoint of the clinician].

The hazards of homologous blood transfusions have been controlled but not eliminated by modern blood banking methods. In addition to the possibility of transmission of infectious diseases, blood transfusion has been reported to induce immunosuppression and thereby impair the host resistance of surgical patients. Experimental and clinical research, particularly in cardiac surgery, have encouraged physicians to accept postoperative anemia. The influence of hemodilution on oxygen supply to the tissues was found to be an increase of local oxygen tension. When hematocrit is progressively lowered under normovolemic conditions, blood cell flux per time and tissue unit is maintained at a hematocrit level as low as 20 vol% as a result of an increase of red blood cell velocity. An increasing number of cardiac operations have been performed upon patients belonging to Jehova's witnesses, inducing an average hematocrit of 11 vol% during extracorporeal circulation. The outcome of these patients was similar to that of patients having received blood transfusion in order to elevate oxygen supply. Some recent studies in critically ill patients demonstrate the importance of oxygen consumption as an important criterion in estimating the effect of oxygen transport. It seems to be proven that, in presence of cardiovascular stability, elevation of the hemoglobin level above 9 g/dl does not result in an increase of oxygen utilization. In accordance with the topical literature we suggest that during the perioperative period a hemoglobin level of 8.5 g/dl will become an accepted transfusion trigger. Particular patients will tolerate even much lower levels.

Fluid replacement

Resuscitation phase - The goal of this phase is to correct the hypotension. Intravenous crystalloid is the first choice of therapy. Surviving Sepsis Campaign recommends 30 ml/kg fluid resuscitation in this phase. Earlier fluid resuscitation is associated with improved survival. Mean arterial pressure should be targeted at more than 65 mmHg. Meanwhile, for early goal directed therapy (EGDT), fluids should be administered within the first six hours of septic shock until central venous pressure (CVP) reaches between 8 and 12 mmHg, with improvement of blood lactate levels, central venous oxygen saturation > 70%, and urine output ≥ 0.5 ml/kg/hour. Higher mean arterial pressures can be used in patients with chronic hypertension in order to reduce the usage of renal replacement therapy. However, if fluid replacement is inadequate in raising blood pressure, then vasopressor have to used. However, there is no definite timing of starting vasopressors. Initiation of vasopressors within the

Serotonin syndrome following metaxalone overdose and therapeutic use of a selective serotonin reuptake inhibitor.

Metaxalone has only recently been associated with serotonin syndrome. The mechanism of action of this centrally acting muscle relaxant is unknown; however, the observation of serotonin syndrome in patients with metaxalone overdose suggests a role in the serotonergic pathway. (Case 1) A 29-year-old woman with overdose of metaxalone presented to the emergency department with altered mental status, seizure-like activity, hyperthermia, rigidity in the lower extremities, myoclonus, and hyperreflexia. Vital signs on arrival include blood pressure of 168/80 mmHg, heart rate of 208 beats per minute (bpm), respirations of 20/min, a temperature of 41.6° C rectally, and room air oxygen saturation of 97%. She was intubated and sedated with benzodiazepines, and actively cooled. Serum paroxetine concentration was 23 (therapeutic range: 20-200) ng/mL, and serum metaxalone concentration was 31 mcg/mL (peak plasma concentrations average 0.9 mcg/mL at 3.3 h following a single oral dose of 400 mg). (Case 2) A 27-year-old man presented to the emergency department with altered mental status, rigidity in his lower extremities, myoclonus, and hyperreflexia. Vital signs on arrival include blood pressure of 158/131 mmHg, heart rate of 126 bpm, respiratory rate of 20 breaths per minute, and temperature of 37.2°C, with oxygen saturation of 98% on room air. His medication list included metaxalone and escitalopram. He was managed aggressively with IV boluses of diazepam, in total 80 mg, in the emergency department. Serum escitalopram concentration was 24 ng/mL with a therapeutic range of 21-64 ng/mL, and serum metaxalone concentration was 58 mcg/mL. These two cases suggest that at supratherapeutic concentrations metaxalone has serotonergic effects. Severe serotonin toxicity may result from metaxalone abuse in individuals using a selective serotonin reuptake inhibitor therapeutically.

Effect of rapid plasma volume expansion during anesthesia induction on haemodynamics and oxygen balance in patients undergoing gastrointestinal surgery.

To investigate the reasonable dose of Voluven for rapid plasma volume expansion during the anaesthesia induction patients receiving gastrointestinal surgery. Sixty patients were randomly divided into three groups (n=20): Group A (5 ml/kg), Group B (7 ml/kg) and Group C (9 ml/kg). HES 130/0.4 was intravenously transfused at a rate of 0.3 ml/kg/min) at 30 min before anaesthesia induction. Besides standard haemodynamic monitoring, cardiac index (CI), systemic vascular resistance index (SVRI) and stroke volume variation (SVV) was continuously detected with the FloTrac/Vigileo system. Haemodynamic variables were recorded immediately before fluid transfusion (T0), immediately before induction (T1), immediately before intubation (T2), immediately after intubation (T3) and 5 min, 10 min, 20 min and 60 min after intubation (T4-T7). Arterial and venous blood was collected for blood gas analysis, Hb and Hct before volume expansion (t0), immediately after volume expansion (t1) and at 1 h after volume expansion (t2). Oxygen delivery (DO2), oxygen extraction ratio (ERO2) and volume expansion rate were calculated. 1) MAP and CI decreased in Group A in T2~T7 and remained changed in Group B and C. 2) CVP increased in three groups after fluid infusion without significant difference. 3) The decrease in SVRI was more obvious in Group B and C than that in Group A after induction and more obvious in Group C than in Group B in T2-T4 and T6~T7. 4) SVV was lower in Group B and C than that in Group A after intubation, and lower in Group C than that in Group B in T3-T6. 5) Hb and Hct decreased after fluid infusion, and the decrease in Hb and Hct was in the order of C>B>A. 6) Volume expansion rate was in the order of C>B>A. 7) ScvO2, PaO2 and DO2 increased in three groups after fluid infusion and the increase in DO2 was in the order of C>B>A. Rapid plasma volume expansion with Voluven at 7-9 ml/kg can prevent haemodynamic fluctuation during anaesthesia induction, maintain the balance between oxygen supply and oxygen consumption during gastrointestinal surgery, and Voluven at 9 ml/kg can improve the oxygen delivery.

Multicenter study of crystalloid boluses and transfusion in pediatric trauma-When to go to blood?

The 9th edition of Advanced Trauma Life Support recommends up to three crystalloid boluses in pediatric trauma patients with consideration of transfusion after the second bolus; however, this approach is debated. We aimed to determine if requirement of more than one fluid bolus predicts the need for transfusion. The 2010 to 2016 highest tier activation patients younger than 15 years from two ACS Level I pediatric trauma centers were identified from prospectively maintained trauma databases. Those with a shock index (heart rate/systolic blood pressure) greater than 0.9 were included. Crystalloid boluses (20 ± 10 mL/kg) and transfusions administered prehospital and within 12 hours of hospital arrival were determined. Univariate and multivariable analyses were conducted to determine association between crystalloid volume and transfusion. Among 208 patients, the mean age was 5 ± 4 years (60% male), 91% sustained blunt injuries, and median (interquartile range) Injury Severity Score was 11 (6,25). Twenty-nine percent received one bolus, 17% received two, and 10% received at least three. Transfusion of any blood product occurred in 50 (24%) patients; mean (range) red blood cells was 23 (0-89) mL/kg, plasma 8 (0-69), and platelets 1 (0-18). The likelihood of transfusion increased logarithmically from 11% to 43% for those requiring 2 or more boluses (Fig. 1). This relationship persisted on multivariable analysis that adjusted for institution, age, and shock index with good discrimination (Area under the Receiver Operating Characteristic, 0.84). Shock index was also strongly associated with transfusion. Almost half of pediatric trauma patients with elevated shock index require transfusion following two crystalloid boluses and the odds of requiring a transfusion plateau at this point in resuscitation. This supports consideration of blood with the second bolus in conjunction with shock index though prospective studies are needed to confirm this and its impact on outcomes. Therapeutic study, level IV.

[Preoperative hypervolemic hemodilution with 6% hydroxyethyl starch 130/0,4 (HES 130/ 0.4) solution as a way of reducing needs for donor blood transfusion].

The efficacy of hypervolemic hemodilution (HHD) in reducing the rate of donor blood transfusion is controversely discussed. The present prospective, randomized, clinical study analyzes the impact of HHD with 6% hydroxyethyl starch (HES) 130/0.4 solution on the rate transfusion, laboratory parameters, and the incidence of complications as compared with those in the control group receiving no preoperative HHD. 80 patients who had undergone total prostatectomy or cystectomy were randomized into 2 groups. Before anesthesia, the HHD group (n=40) received 15 ml/kg of 6% HES 130/0.4 solution. In the HHD and control (n=40) groups, 6% HES 130/0.4 was intraintraoperatively infused in its maximum dose of 33 ml/kg according to the patients' needs. Indicationsf or blood transfusion trigger were Hb <5 g/dl or packed cell volume < 0.24. Laboratory parameters (Hb, PCV, platelets, prothrombin index, prothrombin time, thrombin time, fibrinogen, antithrombin III were measured before surgery, after HHD and 2, 24, and 48 hours after surgery. The mean blood pressure (MBP), heart rate (HR), and central venous pressure (CVP) were determined before surgery, after HHD, and 2 hours postsurgery. Statistical measurements were made in all patients from the HHD and control groups, as well as in a subgroup, in which intraoperative blood loss was greater than 30% of the total blood volume (70 ml/kg body weight). Demographic data and surgical techniques were similar in both groups. After HHD, CVP rose significantly. The changes in MBP and HR were statistically insignificant. There were no complications after HHD. Of the 40 HHD-group patents, 5 needed donor blood transfusion while in the control group blood was transfused to 10 of the 40 patients in the control group. Comparing both groups showed a lower need for blood transfusion in the HHD-group patients than in the controls (10 versus 24 packed red cells). The postoperative Hb values showed no difference between both groups. Preoperative HHD in patients undergoing surgery with expected >30% blood loss leads to decreased needs for blood transfusion. The method is safe and easy-to-use.

Hospital emergency codes

- Major haemorrhage protocol – activated via the Code red system. A peri-arrest call is put out, but the transfusion lab is also alerted. A specified number of units of O-negative packed red blood cells and (sometimes FFP and platelets) are immediately sent to the location of the call. The transfusion lab will crossmatch any saved blood samples for the patient, or await an urgent cross-match sample to be sent. Once this is done, units matching the patient's blood type will be continually sent until the major haemorrhage protocol is stood down.

Blood compatibility testing

Medical uses Blood compatibility testing is routinely performed before a blood transfusion. The full compatibility testing process involves ABO and RhD (Rh factor) typing; screening for antibodies against other blood group systems; and crossmatching, which involves testing the recipient's blood plasma against the donor's red blood cells as a final check for incompatibility. If an unexpected blood group antibody is detected, further testing is warranted to identify the antibody and ensure that the donor blood is negative for the relevant antigen. Serologic crossmatching may be omitted if the recipient's antibody screen is negative, there is no history of clinically significant antibodies, and their ABO/Rh type has been confirmed against historical records or against a second blood sample; and in emergencies, blood may be transfused before any compatibility testing results are available.

[Update on transfusion practice among anesthesiologists and its impact on the surgical patient].

To determine the effectiveness of a new educational program on transfusion practice, directed to the staff of an anesthesia and postoperative recovery service, by evaluating its impact on intraoperative transfusion (IOT). We reviewed the incidence of IOT during the first semesters of 1996 and 2001 for general, urologic, otolaryngologic, maxillofacial, thoracic, and vascular surgery. Other factors such as sex, age, type of intervention, emergency status, duration of operation, and use of blood products were also taken into consideration. A statistically significant overall reduction in IOT occurred between 1996 (4.9%) and 2001 (3.6%). The decrease in transfusions (a reduction of 18.8% in transfused patients) was even greater in general surgery and urology, particularly in scheduled surgery (4.1% in 1996 vs 2.6% in 2001). However, the total use of packed red blood cells did not change inasmuch as the number of units per patient was higher in 2001 (2.8 units/patient) than in 1996 (2.4 units/patient). In emergency surgery, the IOT rate increased from 7.6% in 1996 to 8.1% in 2001. We also noticed a higher rate of multiple transfusions (defined as the use of 5 or more units of packed red blood cells during surgery) in 2001. The introduction of an educational program directed to anesthesiologists has been useful for reducing IOT, although the overall use of blood products has not decreased.

Hypovolemic shock

Class 1: Volume loss up to 15% of total blood volume, approximately 750 mL. Heart rate is minimally elevated or normal. Typically, there is no change in blood pressure, pulse pressure, or respiratory rate. Class 2: Volume loss from 15% to 30% of total blood volume, from 750 mL to 1500 mL. Heart rate and respiratory rate become elevated (100 BPM to 120 BPM, 20 RR to 24 RR). Pulse pressure begins to narrow, but systolic blood pressure may be unchanged to slightly decreased. Class 3: Volume loss from 30% to 40% of total blood volume, from 1500 mL to 2000 mL. A significant drop in blood pressure and changes in mental status occur. Heart rate and respiratory rate are significantly elevated (more than 120 BPM). Urine output declines. Capillary refill is delayed.

[The infusion of packed red cells. Usual difficulties (author's transl)].

This infusion used instead of whole blood has become increasingly common. However in our, as in other french institutions, the volume and the hematocrit of blood contained in each unit varies often notably. In addition, because of their high viscosity packed erythrocytes cannot be transfused rapidly enough. For transfusion in emergency situations and transfusion in operating room, following suggestions could be made to blood banks: --each unit should provide information on its content (volume and hematocrit or hemoglobin content); --units with low blood content should be transfused outside the operating room, whereas units containing high volumes should be reserved for peroperative transfusion in order to reduce charge of manipulation; --packed erythrocytes units should be prepared in order to allow same transfusion rates as whole blood (i.e. an average of 100 ml per minute for one transfusion line); --packed erythrocytes units should contain about 80 ml of plasma for an average total concentrate volume of 260 ml in order to provide enough antibacterial defense components; --units of fresh whole blood should be provided when approximately 150 p. cent of recipient's blood volume has been replaced in order to maintain the critical platelet level.


Angioedema is a type of profound urticaria that can be of drug etiology (not IgE-mediated) and in this case, ACEIs (such as enalapril) are considered the most frequent pharmacological cause, so in this case it would be the correct answer (if we speak in probabilistic terms).

Angioedema is a type of profound urticaria that can be of drug etiology (not IgE-mediated) and in this case, ACEIs (such as enalapril) are considered the most frequent pharmacological cause, so in this case it would be [HIDDEN] (if we speak in probabilistic terms).

A 72-year-old patient comes to the emergency department for presenting with severe and significant lingual angioedema. She does not present associated urticaria and has no history of drug or food allergy. His personal history includes type 2 diabetes mellitus, dyslipidemia, hypertension, hypothyroidism and Parkinson's disease. She is on regular treatment with metformin, simvastatin, enalapril, thyroxine and levodopa. Which of the following drugs is most likely the causal drug of the clinical picture described?

[Therapeutic behavior to follow in the following clinical case: treatment of type 2 diabetes].

A 62-year old woman with obesity, high blood pressure and type 2 diabetes mellitus (DM2) was referred to a Vascular Risk Unit of the Internal Medicine Department due to elevated HbA1C (8.1%) in spite of having taken metformin (850 mg/12h) and glipizide (10 mg/12 h) regularly. She tries to exercise daily (walking 30 min) and has lost weight (from 5 to 12 kg) several times, but always regains what she has lost. Furthermore, she monitors her glucose levels in fasting every two weeks and generally has between 120 and 160 mg/dL. Her high blood pressure is being treated with enalapril/HCTZ and she also takes aspirin 100mg/day and simvastatin 20 mg/day. It is seen in her family background that one brother died suddenly at 50 years of age. Her physical examination shows a BMI of 32.4 Kg/m(2), and she has no edemas in the lower limbs. Her BP is 154/82 mmHg and creatinine 0.9 mg/dL. She has no microalbuminuria and her liver function is normal. What treatment do you think would be the more appropriate? 1 - Add glitazones. 2 - Add incretin mimetics (GLP 1/ DPP-4). 3 - Slow acting insulin.

Extrapyramidal side effect of donepezil hydrochloride in an elderly patient: A case report.

Alzheimer disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction, which is mainly manifested as memory impairment and a reduced ability to self-care, often accompanied by neuropsychiatric and behavioral disorders. Donepezil is the second drug to be approved by the US FDA for the treatment of AD. Of the five FDA-approved drugs for AD treatment, donepezil is currently the most widely used. Here, we report an extrapyramidal adverse reaction to donepezil in an elderly patient with AD. An 87-year-old woman presented with a 1-year history of forgetfulness that was aggravated since the past 2 months. She had a long-term history of multiple major conditions, including hypertension, diabetes, osteoporosis, and arterial plaques. Brain imaging showed age-related changes, and her Mini Mental State Examination score was 20. Other tests revealed no abnormalities apart from multiple thyroid nodules on ultrasonography. She was diagnosed with AD, hypertension, type 2 diabetes mellitus, diabetic neuropathy, osteoporosis, carotid and lower-extremity arterial plaques, thyroid nodules. She was treated with donepezil (5 mg/day), amlodipine besylate (5 mg/day), glimepiride (4 mg/day), methylcobalamin (1.5 mg/day), calcium carbonate D3 (600 mg/day), simvastatin (20 mg/day) and enteric-coated aspirin (100 mg/day). Four days later, she experienced fatigue, panic, sweating, and one episode of vomiting. On the 5th day, she developed increased muscle tension, speech difficulty, and involuntary tremors. Imaging and blood tests revealed no obvious abnormality, and the patient was not receiving psychotropic drugs. An extrapyramidal adverse reaction to donepezil was considered, and the drug was discontinued, after which the symptoms gradually disappeared. Serious adverse reactions to donepezil can occur in elderly patients, who typically require multiple medications for a variety of comorbidities. In particular, extrapyramidal reactions have occurred when donepezil is administered in combination with psychotropic drugs. However, in our patient, an extrapyramidal adverse reaction occurred in the absence of psychotropic drugs. Thus, clinicians must be aware of inter-individual differences in drug actions and possible serious adverse reactions, and carefully monitor these patients to ensure the timely detection of adverse events and their safe treatment.

Cardiovascular effects of levodopa in aged versus younger patients with Parkinson's disease.

The cardiovascular effects of prolonged administration of levodopa were studied in 54 men and women with Parkinson's disease; 23 of them were younger than 70 and 31 were 70 or older. The patients were evaluated clinically before treatment was started and at regular intervals thereafter. The average optimal dosage of levodopa for both age groups was 3.0 and 2.5 gm per day, respectively, during an average treatment period of 20.7 months. Eleven patients showed hypotension (systolic BP of 105 mm Hg or less) that was not related to dosage; in only 6 did the drug have to be permanently discontinued because of syncope; 3 of this group had an associated psychiatric disorder. Four patients had pretreatment hypertension; in 3 the BP fell to normal during therapy; in the remaining patient the hypertension persisted and was successfully treated by an antihypertensive drug. In 5 patients an occasional atrial or ventricular ectopic beat was noted both before and during levodopa therapy but no therapeutic intervention was required. Thirty of the 46 patients with adequate ECG follow-up did not show any significant changes; 5 others showed an increase, and 11 a decrease in myocardial ischemia. Thus the administration of levodopa in elderly patients with or without heart disease is a relatively safe procedure. The only exception would be patients over 70 years of age with a history of previous myocardial infarction. In this group there seems to be a higher incidence of clinically significant hypotension. In such patients, levodopa therapy should be carried out with great caution.

InternalMed_Harrison

Therapy with colchicine, para-aminosalicylate, neomycin, slow-release potassium chloride, anticonvulsant drugs, metformin, phenformin, cytotoxic drugs Alcohol in close relatives and in persons with other organ-specific autoimmune diseases, e.g., thyroid diseases, vitiligo, hypoparathyroidism, and Addison’s disease. It is also associated with hypogammaglobulinemia, with premature graying or blue eyes, and persons of blood group A. An association with human leukocyte antigen (HLA) 3 has been reported in some but not all series and, in those with endocrine disease, with HLA-B8, -B12, and -BW15. Life expectancy is normal in women once regular treatment has begun. Men have a slightly subnormal life expectancy as a result of a higher incidence of carcinoma of the stomach than in control subjects. Gastric output of hydrochloric acid, pepsin, and IF is severely reduced. The serum gastrin level is raised, and serum pepsinogen I levels are low.

InternalMed_Harrison

Centrally acting anticholinergic drugs such as trihexyphenidyl and benztropine were used historically for the treatment of PD, but they lost favor with the introduction of dopaminergic agents. Their major clinical effect is on tremor, although it is not certain that this benefit is superior to what can be obtained with agents such as levodopa and dopamine agonists. Still, they can be helpful in individual patients with severe tremor. Their use is limited particularly in the elderly, due to their propensity to induce a variety of side effects including urinary dysfunction, glaucoma, and particularly cognitive impairment. Carbidopa/levodopa 10/100, 25/100, 25/ 200–1000 mg 250 mg levodopa/d 2–4 times/d Benserazide/levodopa 25/100, 50/200 mg Carbidopa/levodopa CR 25/100, 50/200 mg Benserazide/levodopa 25/200, 25/250 mg MDS Parcopa 10/100, 25/100, 25/250 Carbidopa/levodopa/ 12.5/50/200, entacapone 18.75/75/200, 25/100/200, 31.25/125/200, 37.5/150/200, 50/200/200 mg

Liraglutide-associated acute pancreatitis.

A case of acute pancreatitis associated with liraglutide is reported. A 53-year-old African-American man (height, 185.4 cm; weight, 108.6 kg) with type 2 diabetes mellitus arrived at the emergency department (ED) with new-onset intolerable abdominal pain in the right upper quadrant and left upper quadrant that had appeared suddenly and lasted two to three hours. He had nausea but no vomiting, with tenderness in the epigastric region. In the ED, his serum amylase concentration was found to be extremely elevated (3,963 units/L), as was his serum lipase concentration (>15,000 units/L). In addition to type 2 diabetes, his medical history included hyperlipidemia, hypertension, peripheral neuropathy, erectile dysfunction, and obesity. His home medications included aspirin 81 mg orally daily, metformin 1000 mg orally every morning and 1500 mg every evening, simvastatin 80 mg orally daily at bedtime, tadalafil 20 mg orally as needed, glimepiride 4 mg orally twice daily, and liraglutide 1.2 mg subcutaneously daily. Two months before his arrival to the ED, the patient's dosage of liraglutide was increased from 0.6 to 1.2 mg subcutaneously daily. Radiographic data were obtained, and acute pancreatitis was diagnosed. Liraglutide was discontinued indefinitely after ruling out elevated triglycerides as the cause of pancreatitis. The patient was initiated on standard therapy for acute pancreatitis and discharged eight days later with complete resolution of symptoms and normal laboratory test values. A 53-year-old man with type 2 diabetes mellitus developed a probable case of liraglutide-induced acute pancreatitis after receiving the drug for approximately two months.

Levodopa-induced dyskinesia

Nicotine (administered by dermal adhesive patches) has also been shown to improve Levodopa-induced dyskinesia and other PD symptoms. Patients with prominent dyskinesia resulting from high doses of antiparkinsonian medications may benefit from deep brain stimulation (DBS), which may benefit the patient in two ways: 1) DBS theoretically allows a reduction in l-DOPA dosage of 50–60% (tackling the underlying cause); 2) DBS treatment itself (in the subthalamic nucleus or globus pallidus) has been shown to reduce dyskinesia. Mavoglurant is also currently studied by Novartis for the treatment of this disease. On August 24, 2017 the FDA approved a drug to treat levodopa-induced dyskinesia for Parkinson's patients. The drug, Gocovri, is amantadine manufactured by Adamas Pharmaceuticals. It is the first FDA approved treatment for this condition. References External links Parkinson's disease

[Severe parkinsonism due to metoclopramide: the importance of early recognition].

In this article, we present 3 women aged 73, 85 and 88 years who developed metoclopramide-induced parkinsonism. Shortly after starting metoclopramide, bradykinesia and rigidity developed in all 3 patients; tremor and postural instability in 2 of them. We discontinued the metoclopramide after 3-6 months; 2 of the patients had fully recovered 4-6 months later. The 3rd patient died from pneumonia, however, 2 months after discontinuation. Metoclopramide, a dopamine D2-antagonist, is a frequently prescribed anti-emetic drug; however, evidence of its efficacy is limited. In many patients, domperidone, another dopamine D2-antagonist, seems to be a better alternative. Movement disorders due to domperidone are uncommon, presumably because it does not cross the blood-brain barrier. It is likely that metoclopramide-induced parkinsonism is not uncommon; however, it is under-recognized. Risk factors are female sex, advanced age, diabetes mellitus and polypharmacy. Follow-up on patients using metoclopramide is advised.

Hypersensitivity to intravenous ondansetron: a case report.

Ondansetron, a 5-hydroxytryptamine3 receptor antagonist widely used in the prevention and treatment of chemotherapy-induced nausea and vomiting, is associated with various unusual adverse drug reactions. In this paper, we describe a hypersensitivity reaction to a single intravenous dose of ondansetron. A 19-year-old woman presented to the emergency department of our institute with 3-4 episodes of nausea, vomiting and epigastric distress. She had a diagnosis of polycystic ovarian disease and had been on treatment with cyproterone acetate 2 mg, ethinyl estradiol 0.035 mg, finasteride 5 mg and metformin 500 mg for a month. She had been taking oral roxithromycin 500 mg per day for the past 3 days for treatment of a mild upper respiratory tract infection. She also occasionally took rabeprazole 10 mg for gastritis which had worsened after treatment with roxithromycin. She was treated with a single 4 mg dose of ondansetron intravenously. She immediately developed urticaria, which was treated with intravenous dexamethasone 4 mg and chlorpheniramine maleate 20 mg. The reaction abated within a few minutes and she was discharged within an hour. She was asymptomatic at 72 hours of follow-up.She had no history of ondansetron exposure, or drug or food allergies. On the Naranjo's causality assessment scale, the adverse event was 6 indicating a "probable" reaction to ondansetron. 5-hydroxytryptamine3 receptor antagonists have been associated with life-threatening adverse reactions such as hypotension, seizures and anaphylaxis. The wide availability of these drugs in India has promoted their off label use in the treatment of gastritis, migraine and so on. Our case represents an off label use in a patient who could have been treated with a safer drug.Some authors have suggested that anaphylaxis may be a class effect while others think it may be drug specific. In our case, the reaction could be either anaphylaxis or anaphylactoid, but the latter seems more likely given the history of absence of prior sensitization. Other components of the drug, such as solvent, also need to be considered as a cause of this reaction. Considering all of the existing evidence, we need to be more cautious while using ondansetron and also to be aware of the various unusual side effects, especially when used in an out-of-hospital set-up.Our case report underscores the importance of physicians judiciously using the drug, particularly in the outpatient setting so as to reduce the incidence of avoidable adverse drug reactions.

[Parkinsonism probably induced by manganese].

In all cases of young persons with clinical Parkinson s disease it should be suspected that it is secondary to some primary disorder. Therefore a battery of diagnostic tests should be done before classification as idiopathic Parkinson s disease. A 31 year old woman whose only previous illness had been Graves disease. She complained of difficulty with movements of her right arm and leg for some months (she had problems with walking and with rapid, repeated movements of her right hand). She also complained of tremor of her right limbs at rest. She denied taking drugs, having dysphagia, dysarthria, visual changes or sphincter disorders. Neurological examination showed her to have monotonous speech, slight facial hypomimia, slight reduction in spontaneous blinking, walking with less swing of her right arm; postural tremor of both arms, worse on the right; bradykinesia (2/4) of both right limbs and rigidity (1/4), axial and of the right limbs. The results of all the investigations done to rule out secondary Parkinsonism were normal, except for the plasma manganese level which was raised, although it returned to normal when the probable source of exposure to this metal was removed. However, the alterations of movement only disappeared after treatment with levodopa was started. In cases of Parkinsonism in young adults secondary causes should always be rules out, such as exposure to certain metals.

Metformin-induced lactic acidosis: a case series.

Unlike other agents used in the treatment of type 2 diabetes mellitus, metformin has been shown to reduce mortality in obese patients. It is therefore being increasingly used in higher doses. The major concern of many physicians is a possible risk of lactic acidosis. The reported frequency of metformin related lactic acidosis is 0.05 per 1000 patient-years; some authors advocate that this rate is equal in those patients not taking metformin. We present two case reports of metformin-associated lactic acidosis. The first case is a 77 year old female with a past medical history of hypertension and type 2 diabetes mellitus who had recently been prescribed metformin (3 g/day), perindopril and acetylsalicylic acid. She was admitted to the emergency department two weeks later with abdominal pain and psychomotor agitation. Physical examination revealed only signs of poor perfusion. Laboratory evaluation revealed hyperkalemia, elevated creatinine and blood urea nitrogen and mild leukocytosis. Arterial blood gases showed severe lactic acidemia. She was admitted to the intensive care unit. Vasopressor and ventilatory support was initiated and continuous venovenous hemodiafiltration was instituted. Twenty-four hours later, full clinical recovery was observed, with return to a normal serum lactate level. The patient was discharged from the intensive care unit on the sixth day. The second patient is a 69 year old male with a past medical history of hypertension, type 2 diabetes mellitus and ischemic heart disease who was on metformin (4 g/day), glycazide, acetylsalicylic acid and isosorbide dinitrate. He was admitted to the emergency department in shock with extreme bradycardia. Initial evaluation revealed severe lactic acidosis and elevated creatinine and urea. The patient was admitted to the Intensive Care Unit and commenced on continuous venovenous hemodiafiltration in addition to other supportive measures. A progressive recovery was observed and he was discharged from the intensive care unit on the seventh day. We present two case reports of severe lactic acidosis most probably associated with high doses of metformin in patients with no known contraindications for metformin prescription. In both patients no other condition was identified to cause such severe lactic acidosis. Although controversial, lactic acidosis should be considered in patients taking metformin.

How to prevent and treat pharmacological hypoglycemias.

A 58 year-old woman with type 2 diabetes diagnosed 3 years before came to our clinic. Her treatment was metformin 850 mg every 12 hours and glimepiride 4 mg every 24 hours. After the initiation of glimepiride 9 months before her weight has increased 5 kg, and she suffers frequent hypoglycemias which have affected her while driving. Her BMI is 35.5 kg/m². She has a normal eye fund exam. She has hypertension treated with telmisartán and hidroclorotiazide with adequate control, and also hypercholesterolemia treated with atorvastatine 40 mg every 24 hours. Her blood test shows an HbA1c of 7.0%, normal values of microalbuminuria, total cholesterol 149 mg/dl, HDL cholesterol 52 mg/dl, LDL cholesterol 98 mg/dl and triglycerides 123 mg/dl. Her blood pressure is 129/81 mmHg, there was no orthostatic hypotension, and her peripheral neurological examination shows normal results. In summary, our case is a young woman with type 2 diabetes and obesity, without chronic complications and which has frequent hypoglycaemia. How must this woman be evaluated and treated?

Sitagliptin/simvastatin

History In 1991, Merck & Co's simvastatin was approved as an HMG-COA inhibitor to lower the levels of LDL cholesterol. In 2006, Merck & Co's sitagliptin was approved by the FDA for treatment of diabetes mellitus type 2. The patent for simvastatin expired in 2006 and many companies began to create a generic product of simvastatin. By creating a combined-dosage form of simvastatin and sitagliptin, Merck was able to increase their sales of simvastatin while meeting the need of patients who take both simvastatin and sitagliptin. Regulation Juvisync was the first product to combine a cholesterol lowering drug with a type 2 diabetes drug in the same tablet. Due to the potential for patients to need different doses of the two drugs, different dosage strengths were approved. These doses are for sitagliptin/simvastatin of 100 mg/10 mg, 100 mg/20 mg, 100 mg/40 mg, 50 mg/10 mg, 50 mg/20 mg, or 50 mg/40 mg. Nonclinical toxicology

Drugs inducing or aggravating parkinsonism: a review.

Drug-induced parkinsonism (DIP) is frequent. The list of drugs able to induce parkinsonism is long and probably incomplete, because new drugs, with previously unknown antidopaminergic activity, are constantly being added. Not all the drugs have the same potency for inducing parkinsonism. We classify these drugs in three groups: (1) drugs with obvious antidopaminergic activity which regularly induce parkinsonism; (2) drugs able to induce parkinsonism in particular individuals and (3) drugs which may aggravate Parkinson's disease treated with levodopa. The reports of isolated cases of parkinsonism induced by widely-used drugs (drugs in group 2) may be the result of either an idiosyncratic side effect or a misdiagnosis of parkinsonism. The antidopaminergic activity of the drugs of this group is weak and not sufficiently demonstrated. Maybe, in these cases, the blockage of other neurotransmitters different from dopamine plays a role in the induction of parkinsonism. Probably, the number of patients with DIP is higher than reported or detected, because many patients suffer from weak symptoms that quickly disappear after drug withdrawal. One of the main points of interest is knowing the list, because all these drugs, specially those of group 1, should be avoided or used with caution in the treatment of some common symptomatic problems in patients with Parkinson's disease, such as depression, arterial hypertension, diabetes mellitus and cardiac disorders. The precautions should extent to other populations especially susceptible to suffer from DIP, such as the elderly or patients with other neurodegenerative disorders, such as Alzheimer's disease.

Pharmacology_Katzung

E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. TABLE 66–1 Important drug interactions. HMG-CoA reductase inhibitors (statins) (cont.) Iron Binds with drugs in gastrointestinal tract, reducing absorption. Levodopa Levodopa degraded in gut prior to reaching sites of absorption. Agents that alter gastrointestinal motility may alter degree of intraluminal degradation. Antiparkinsonism effect of levodopa susceptible to inhibition by other drugs. Lithium Renal lithium excretion sensitive to changes in sodium balance. (Sodium depletion tends to cause lithium retention.) Susceptible to drugs enhancing central nervous system lithium toxicity.

Substantia nigra

Levodopa The substantia nigra is the target of chemical therapeutics for the treatment of Parkinson's disease. Levodopa (commonly referred to as L-DOPA), the dopamine precursor, is the most commonly prescribed medication for Parkinson's disease, despite controversy concerning the neurotoxicity of dopamine and L-DOPA. The drug is especially effective in treating patients in the early stages of Parkinson's, although it does lose its efficacy over time. Levodopa can cross the blood–brain barrier and increases dopamine levels in the substantia nigra, thus alleviating the symptoms of Parkinson's disease. The drawback of levodopa treatment is that it treats the symptoms of Parkinson's (low dopamine levels), rather than the cause (the death of dopaminergic neurons in the substantia nigra). MPTP

[Hypothyroidism concealed by Parkinson's disease].

Although it is commonly recognised that diseases of the thyroids can simulate extrapyramidal disorders, a review of the causes of Parkinsonism in the neurology literature shows that they are not usually mentioned or, if so, only very briefly. The development of hypothyroidism in a patient with Parkinson s disease can go undetected, since the course of both diseases can involve similar clinical features. Generally speaking there is always an insistence on the need to conduct a thyroidal hormone study in any patient with symptoms of Parkinson, but no emphasis is put on the need to continue to rule out dysthyroidism throughout the natural course of the disease, in spite of the fact that the concurrence of both pathological conditions can be high and that, in the same way hypothyroidism can simulate Parkinson s disease, the latter can also conceal hypothyroidism. We report the case of a female patient who had been suffering from Parkinson s disease for 17 years and started to present on off fluctuations that did not respond to therapy. Hypothyroidism was observed and the hormone replacement therapy used to resolve the problem allowed the Parkinsonian fluctuations to be controlled. We believe that it is very wise to suspect hypothyroidism in patients known to be suffering from Parkinson s disease, and especially so in cases where the clinical condition worsens and symptoms no longer respond properly to antiparkinsonian treatment. These observations stress the possible role played by thyroid hormones in dopaminergic metabolism and vice versa.

Metformin-Associated Lactic Acidosis: A Case Report.

A 54-year-old woman with type 2 diabetes mellitus, hypertension, and peripheral vascular disease developed life-threatening lactic acidosis during treatment with metformin for type 2 diabetes. The woman received metformin at 1000 mg orally twice a day for type 2 diabetes. She presented to our emergency department with a 3-day history of severe watery diarrhea, nausea, and vomiting. Her grandson whom she cared for had gastroenteritis several days prior to the onset of her symptoms. She was confused and hypotensive with a blood pressure of 70/39 mmHg. Her initial laboratory findings were remarkable with an arterial blood gas pH 6.57, HCO[Formula: see text] 2 mEq/L, anion gap 30 mmol/L, and lactate 16.3 mmol/L. She was diagnosed with severe lactic acidosis. Metformin was discontinued. Upon arrival in the emergency department, she became unresponsive and experienced a pulseless electrical activity cardiac arrest. After resuscitation, her severe acidemia persisted despite aggressive intervention with volume resuscitation and vasopressors, leading to the initiation of renal replacement therapy. After multiple dialysis treatments, her severe acidemia resolved. Serum metformin concentration from presentation ultimately returned to 42 mcg/mL (therapeutic concentration: 1-2 mcg/mL). She was discharged from the hospital on day 15 without any neurologic complications. A Naranjo assessment score of 8 was obtained, indicating a probable relationship between the patient's lactic acidosis and her use of the suspect drug.

Gout and Levodopa: An unknown adverse effect?

We report the case of a 77-year-old man with Parkinson's disease (PD) who experimented for the first time gout crisis after the initiation of levodopa. Levodopa was withdrawn, and colchicine and allopurinol were initiated to treat the gout crisis. Because of PD progression, levodopa was reintroduced, and the patient presented relapse of gout flare. To further explore the association between gout and levodopa, we extracted and synthetized all Individual Case Safety Reports of gout associated with levodopa in the World Health Organization pharmacovigilance database, VigiBase<sup®</sup , up to April 2021. 43 cases of gout were reported in VigiBase<sup®</sup with drugs from N04BA ATC class. Levodopa was suspected in fifteen cases among which improvement was noticed in six cases (two after levodopa withdrawal, two despite treatment continuation, and two cases lacking details about action taken with levodopa); three cases did not recover; in the remaining six cases, evolution was not known. "Hyperuricemia" was not mentioned in the Summary of Product Characteristics of medicine containing levodopa; however, "abnormality biologics test with uric acid" was mentioned. Despite few cases of recovery after reduced doses of levodopa, the above-described case of positive reintroduction was an argument in favor of the role of levodopa in gout flare. This study highlights a potential association between levodopa and gout through an analysis of the cases reported in the WHO pharmacovigilance database.

Carbidopa/levodopa/entacapone

Carbidopa/levodopa/entacapone may be combined with the drugs rasagiline or selegiline. These drugs are a different type of MAO inhibitor known as selective MAO inhibitors that are often prescribed for Parkinson's disease. Many drug interactions involving selegiline are theoretical, primarily based on interactions with non-selective MAO inhibitors; at oral doses the risk of these interactions may be very low. However, transdermal selegiline, known by its trade name Emsam, is still contraindicated. Transdermal selegiline results in higher plasma levels at which it behaves like a non-selective MAO inhibitor. Concominant use of entacapone, a component of carbidopa/levodopa/entacapone, with MAO inhibitors may increase toxicity of MAO inhibitors. Levodopa, also a component of carbidopa/levodopa/entacapone, in combination with MAO inhibitors may result in hypertensive reactions. Mechanism of action

Lump in the throat - a case study.

Jack, aged 66 years, presented to his general practitioner with a foreign body sensation in his throat and altered voice, which developed over 30 minutes. He was otherwise well, having no other new symptoms or recent alterations to medication. He had not eaten anything unusual. He had hypertension, type 2 diabetes, stable ischaemic heart disease, urolithiasis and benign prostatic hypertrophy. His regular medication was metformin, rosuvastatin, carvedilol, candesartan (last 5 years) and saxagliptin (last 6 months). He had no allergies but was intolerant of ramipril due to cough. There was no family history of note. On examination he had no itch or rash, or swelling of the tongue, lips, cheek or neck. However, there was oedema of the soft palate and uvula. He was maintaining his airway, saturating at 98%, and his chest was clear. He was afebrile and systemically well.

Dihydroergocryptine

The relatively long half-life and lack of dietary influence of dihydroergocriptine is considered to contribute to the compound's effectiveness in Parkinson's disease, particularly since it allows for more continuous stimulation of brain dopaminergic receptors than short-acting drugs such as levodopa. DHEC is also proven to be a safe and effective in improving symptoms in Parkinson's patients. Motor improvements in Parkinson's patients are usually observed in patients who take at least a mean daily dose of approximately 40 mg. Patients on DHEC demonstrate a better score than if they were on levodopa on the Webster scale, a standardized rating scale of Parkinson's Disease symptoms such as gait parameters and dyskinesia. Another clinical study has shown that DHEC had superior efficacy in reducing the clinical and motorcomplications associated with long-term levodopa use, as well as in reducing the incidence and severity of adverse effects.

History of Parkinson's disease

History of treatments

Befiradol

Befiradol was discovered and developed by Pierre Fabre Médicament, a French pharmaceuticals company. In September 2013, befiradol was out-licensed to Neurolixis, a California-based biotechnology company. Neurolixis announced that it intends to re-purpose befiradol for the treatment of levodopa-induced dyskinesia in Parkinson's disease. In support of this indication, Neurolixis received several research grants from the Michael J. Fox Foundation and preclinical data was published describing the activity of befiradol in animal models of Parkinson's disease. In January 2018, the British charity Parkinson's UK announced that it had awarded Neurolixis a grant to advance development of befiradol up to clinical phase in Parkinson's disease patients. In March 2019, Neurolixis announced that the US Food and Drug Administration (FDA) gave a positive response to Neurolixis' Investigational New Drug (IND) application for NLX-112 to be tested in a Phase 2 clinical study in Parkinson's disease

The Rush Limbaugh Show

Michael J. Fox controversy On the October 23, 2006, broadcast of his radio show, Limbaugh imitated on the "DittoCam" (the webcam for Web site subscribers to see him on the air) the physical symptoms actor Michael J. Fox showed in a television commercial raising awareness of Parkinson's disease. He said "[Fox] is exaggerating the effects of the disease. He's moving all around and shaking and it's purely an act ... This is really shameless of Michael J. Fox. Either he didn't take his medication or he's acting." Three days later, on October 26, Limbaugh denied that he was ridiculing Fox, stating that, after seeing Fox without his medication, "I [was] stunned because I [had] never seen Michael J. Fox that way." Limbaugh said that he was "mov[ing] around like [Fox] does, but never once was I making fun of him. I was trying to illustrate for my audience watching on the Dittocam what I had seen."

Vildagliptin

Vildagliptin, sold under the brand name Galvus among others, is an oral anti-hyperglycemic agent (anti-diabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1 and GIP by DPP-4, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas. Vildagliptin has been shown to reduce hyperglycemia in type 2 diabetes mellitus. Combination with metformin The European Medicines Agency has also approved a combination of vildagliptin and metformin, vildagliptin/metformin (Eucreas by Novartis) as an oral treatment for type-2 diabetes. Adverse effects Adverse effects observed in clinical trials include nausea, hypoglycemia, tremor, headache and dizziness. Rare cases of hepatoxicity have been reported.

Levodopa-induced dyskinesia

In the context of Parkinson's disease (PD), dyskinesia is often the result of long-term dopamine therapy. These motor fluctuations occur in up to 80% of PD patients after 5–10 years of l-DOPA treatment, with the percentage of affected patients increasing over time. Based on the relationship with levodopa dosing, dyskinesia most commonly occurs at the time of peak l-DOPA plasma concentrations and is thus referred to as peak-dose dyskinesia (PDD). As patients advance, they may present with symptoms of diphasic dyskinesia (DD), which occurs when the drug concentration rises or falls. If dyskinesia becomes too severe or impairs the patient's quality of life, a reduction in l-Dopa might be necessary, however this may be accompanied by a worsening of motor performance. Therefore, once established, LID is difficult to treat. Amongst pharmacological treatments, N-methyl-D-aspartate (NMDA) antagonist, (a glutamate receptor), amantadine, has been proven to be clinically effective in a small

Neurology_Adams

The once-held notion that the administration of l-dopa early in the disease might reduce the period over which it remains effective has been largely dispelled, but some neurologists continue to adhere to this idea. Cedarbaum and colleagues, who reviewed the course of the illness in 307 patients over a 7-year period, found no evidence that the early initiation of l-dopa treatment predisposed to the development of fluctuations in motor response or to dyskinesia and dementia. In fact, the findings of the “Elldopa” trial by The Parkinson Study Group (2004) were that functional and other measures were better in patients who had taken l-dopa for 40 weeks and then stopped the medications than in those who received no medication. This was tentatively taken to endorse the opposite notion, that l-dopa was somehow protective for the progress of disease but the alternative explanation was that the drug had a symptomatic carry over effect after it was stopped. This was addressed further in a trial

Which drugs cause treatment-related problems? Analysis of 10,672 problems within the outpatient setting.

Treatment-related problems (TRPs) may pose risks for patients if unaddressed. With the increased complexity of health care, it is important to target pharmacists' efforts to patients that are at high risk for TRPs. The present study aimed to identify medications most commonly associated with TRPs. Outpatient departments of five public and teaching hospitals in Jordan. TRPs and drugs most commonly implicated with TRPs were assessed for patients recruited from outpatient clinics in five major hospitals in Jordan using a standardized and validated pharmaceutical care manual. Drugs associated with different types of TRPs. Ultimately, 2,747 patients, with a total of 10,672 TRPs, were included in the study. The medication groups most commonly associated with TRPs were cardiovascular (53.0%), endocrine (18.1%), and gastrointestinal (7.7%) drugs. The most common specific drugs associated with TRPs from any category were atorvastatin (12.5%), metformin (8.5%), simvastatin (6.2%), and enalapril (5.9%). Cardiovascular medications were the most common drugs implicated with multiple subtypes of TRPs - most commonly, allergic reaction or undesirable effect (88.5%), drug product not available (87.3%), safety interaction issues (81.8%), a need for additional or more frequent monitoring (78.0%), and more effective drugs available (77.2%). Hypertension, diabetes mellitus, and dyslipidemia were the most common diseases associated with different subtypes of TRPs. The present study identified high-risk drugs for TRPs, which can be used as identification of targeting approach TRPs. Such an approach would improve care provided to patients and can inform health care policies.

Parkinson's disease, treatment choice and survival over time.

We compared Monoamine oxidase B (MAO-B) - and dopamine agonist (DA) monotherapy patients with respect to survival, considering gender, age, first prescriber's specialty and relevant co-morbidity, and compared their specialist health care contacts and hospitalizations. With data from health registries, we considered 21,047 patients without redemptions for MAO-B, DA or levodopa 6 months prior to their first MAO-B or DA redemption in 2006 and followed them throughout 2016. We considered Cox proportional hazard regression models for comparing the risk of death among MAO-B and DA monotherapy patients. MAO-B-users had a higher mortality than DA-users, [HR: 1.587, 95% CI: 1.056; 2.384] for patients under 74 years. There was an increased mortality risk with increasing age, women had lower risk than men and previous diabetes-, antihypertensive-, and cardiac drug users had higher risk compared to patients without such history. Previous use of hypothyroid drugs and having a specialist as first prescriber were not significant risk factors.Among patients without hospitalizations 13.7% died, while among patients who spent at least one night in hospital 36.73% died. The median duration of a hospitalization among those who died and not were 17.5 and 7 days. Among the small proportion with specialist health care contacts circulatory- and respiratory-system diseases were the most frequent cause of contact. DAs were most frequently given when initiating Parkinson's treatment. DA-users had a lower mortality risk compared to MAO-B-users and less specialist health care contact.

Neurolixis

and Drug Administration (FDA) gave a positive response to Neurolixis' Investigational New Drug (IND) application for befiradol to be tested in a Phase 2 clinical study in Parkinson's disease patients with troublesome Levodopa-induced dyskinesia. Studies published in 2020 using non-human primate models of Parkinson's disease, (MPTP-treated marmosets and MPTP-treated macaques), found that befiradol potently reduced Levodopa-induced dyskinesia at oral doses as low as 0.1 to 0.4 mg/kg.

Effect of levodopa on orthostatic and postprandial hypotension in elderly Parkinsonian patients.

This study describes orthostatic and postprandial hypotension in elderly Parkinsonian patients and evaluates the effect of levodopa therapy on orthostatic and postprandial hypotension in these patients. Seventeen elderly patients with a clinical diagnosis of Parkinson's disease or Parkinsonism based on the U.K. Parkinson's Disease Society Brain Bank criteria (age range, 66-84 years) participated in the study. Blood pressure was continuously monitored during standardized standing and meal tests, after starting 125-mg b.i.d. doses of levodopa/benserazide (Madopar) or placebo, in a double-blind, randomized, cross-over design. Seventeen age- and sex-matched healthy subjects served as controls. Orthostatic hypotension was infrequently found in Parkinsonian patients (13%) and healthy subjects (6%; p =.58, between groups), whereas postprandial hypotension was more frequent in Parkinsonian patients (82%) than in healthy subjects (41%; p <.05, between groups). Doses of levodopa/benserazide, administered 2 times per day, did not result in significantly larger blood pressure decreases after standing or eating, or in higher frequencies of orthostatic or postprandial hypotension in the Parkinsonian group. Postprandial hypotension was related to disease severity (r = -.56, p <.05). Postprandial hypotension, but not orthostatic hypotension, was more common in elderly Parkinsonian patients than in healthy subjects. Therapy with 125-mg b.i.d. doses of levodopa/benserazide did not significantly aggravate orthostatic or postprandial hypotension.