Metformin-Induced Lactic Acidosis (MILA): Review of current diagnostic paradigm

A new diagnostic paradigm has been proposed to better categorize causes of Metformin-Associated Lactic Acidosis (MALA). The diagnostic criteria defines a link between Metformin and lactic acidosis if lactate is >5 mmol/L, Ph < 7.35 and Metformin assay > 5mg/L. Metformin assays are not readily available in emergency departments including nationwide Veteran’s Affairs Hospitals; thereby making this proposed classification tool difficult to use in today’s clinical practice. We describe a case report of a 45-year-old male, who took twice the amount of Metformin prescribed and presented with Metformin-induced lactic acidosis. According to the new criterion, our case would be classified as “Lactic Acidosis in Metformin-Treated Patients (LAMT).” However, the term LAMT does not distinguish between a septic patient taking Metformin with lactic acidosis, and a patient who ingested toxic amounts of Metformin and has lactic acidosis (in absence of Metformin assay). Our case highlights the importance of medication reconciliation done on arrival to emergency department. Timing and dosing of Metformin in patients who present to the emergency department with lactic acidosis may cinch the diagnosis of Metformin-Induced Lactic Acidosis (MILA) in the absence of a Metformin assay but in the right clinical context.     

An under-recognized complication of treatment of acute severe asthma

A 39-year-old man presented to the emergency department (ED) in severe respiratory distress. He had a prior diagnosis of brittle asthma and had been admitted on several occasions but never previously ventilated. Therapy given in the first 3 hours of arrival included nebulized salbutamol (5 mg, x5), ipratropium bromide (0.5 mg), intravenous hydrocortisone (200 mg), and magnesium sulfate (2 g). His arterial blood gases continued to deteriorate. He was then given an intravenous bolus of salbutamol (250 microg) and heliox via facemask. His worsening status necessitated invasive ventilation. His hypercapnia and resultant respiratory acidosis improved rapidly, but there was a concurrent accumulation of lactic acid resulting in acidemia. This patient had lactic acidosis as a direct effect of administration of salbutamol. The development of hazardous salbutamol-induced toxicity in acute severe asthma is discussed.     

A clinical case of development of lactic acid acidosis in a diabetic patient taking metformin

Metformin is a biguanide. Due to its effects in suppressing the hepatic production of endogenous glucose and in increasing insulin sensitivity in adipose tissue and skeletal muscle, the agent is used particularly in type 2 diabetes mellitus and metabolic syndrome, in which insulin resistance is especially pronounced. Lactic acidosis is one of the most important side effects of metformin. A male patient, born in 1923, was admitted to the emergency unit of our hospital for sudden vertigo, weakness, dyspnea, cyanosis, and lethargy. His history data showed that the patient had been suffering from type 2 diabetes mellitus for 10 years and taking Glargin (insulin), 12 U/kg, once daily and Glucophage (metformin), 850 mg thrice daily. The patient's general condition was fair; stupor, time and spatial orientation were absent. Analysis of arterial blood gases showed the presence of metabolic acidosis, hypokalemia, hypoxemia, and hypercapnia. Thereafter the patient was transferred to the intensive care unit of the hospital; intubated and connected to a T-bird ventilation apparatus. On the following day, an analysis of arterial blood gases indicated the proximity of the results to their physiological parameters. Ventilation was stopped; and monitoring of the patient continued by following the T-shape type of ventilation discontinuation. There were no X-ray signs of pneumonia or pulmonary edema. On the same day, the patient was extubated and oxygen inhalation in a dose of L/min was continued through a mask. On day 4 since therapy was initiated, the patient's vital signs, serum sugar and lactate levels became normal. By determining a new treatment regimen, the patient was discharged from the intensive care unit. Dyspnea, acidosis, and hypoxia developed in the patient resulted from lactic acidosis caused by the use of metformin. It should be remembered that dyspnea, acidosis, and hypoxia, which suddenly developed in metformin-treated patients with type 2 diabetes mellitus, may be caused by lactic acidosis.     

Take my breath away: a case of lactic acidosis in an asthma exacerbation

A 36-year-old male with a history of chronic asthma presented to an emergency department with shortness of breath consistent with an asthma exacerbation. He had persistent tachypnea following inhaled bronchodilator treatment; thus, the workup and differential diagnosis were expanded. He was found to have a mixed respiratory alkalosis and metabolic acidosis with elevated serum lactate without an obvious cause and was admitted to hospital. His case was reviewed, and the lactic acidosis was thought to be caused by inhaled β2-agonist use. Emergency physicians should be aware of the potential side effects of inhaled β2-agonists as lactic acidosis may complicate clinical assessment and management of asthma exacerbations and lead to unnecessary and potentially dangerous escalations in therapy.     

Is lactic acidosis predictive of outcomes in pediatric diabetic ketoacidosis?

ObjectivesThe objective of this study was to investigate the significance and prevalence of lactic acidosis in pediatric diabetic ketoacidosis (DKA) presenting to the emergency department.MethodsA retrospective cohort study of children (age ≤ 21 years) presenting to a tertiary care emergency department in DKA from December 1, 2015 to December 1, 2018. Patients needed to have DKA requiring admission to the pediatric intensive care unit and have had a lactate level collected while in the emergency department to be included.Results92 patients resulting in 113 encounters had DKA and a lactate level collected in the emergency department. The mean lactate level was 3.5 mmol/L (±SD 2.1). 72 (63.7%) encounters had lactic acidosis (p < 0.001). There was no significant association between the presence of lactic acidosis and pediatric intensive care unit length of stay (p = 0.321), hospital length of stay (p = 0.426), morbidity (p = 0.552) and mortality (p = 1.000). Initial glucose levels were significantly higher in the patients presenting with lactic acidosis (p = 0.001).ConclusionsLactic acidosis is a common finding in pediatric DKA patients presenting to the emergency department. Serum lactate alone should not be used as an outcome predictor in pediatric DKA.     

Metformin-induced lactic acidosis: no one left behind

Metformin is a safe drug when correctly used in properly selected patients. In real life, however, associated lactic acidosis has been repeatedly, although rarely, reported. The term metformin-induced lactic acidosis refers to cases that cannot be explained by any major risk factor other than drug accumulation, usually due to renal failure. Treatment consists of vital function support and drug removal, mainly achieved by renal replacement therapy. Despite dramatic clinical presentation, the prognosis of metformin-induced lactic acidosis is usually surprisingly good.     

Survival from profound alcohol-related lactic acidosis.

We present the case of a patient with profound alcohol-related lactic acidosis (lactate = 16.1 mmol/L; pH = 6.67) associated with a multitude of metabolic derangements who made a remarkable recovery following aggressive management. The patient was in extremis upon arrival in the emergency department (ED), and resuscitation was begun immediately. While in the ED, the problem list generated included: acute alcohol intoxication, severe lactic acidosis, dehydration, hypothermia, hypoglycemia, acute renal insufficiency, and hepatic failure. Resuscitation continued in the intensive care unit with remarkable improvement and satisfactory outcome. In this patient, the severe lactic acidosis and associated abnormalities were all attributed to acute and chronic effects of ethanol. A brief summary of the proposed mechanism by which these metabolic derangements developed and an outline of her management follows.     

Do risk factors for lactic acidosis influence dosing of metformin?

BACKGROUND: Metformin is commonly prescribed to treat type 2 diabetes mellitus, however it is associated with the potentially lethal condition of lactic acidosis. Prescribing guidelines have been developed to minimize the risk of lactic acidosis development, although some suggest they are inappropriate and have created confusion amongst prescribers. The aim of this study was to investigate whether metformin dose was influenced by the presence of risk factors for lactic acidosis. METHODS: The study was prospective, and retrieved information from patients admitted to hospital who were prescribed metformin at their time of admission. RESULTS: Eighty-three patients were included in the study, 60 of whom had a least one risk factor for lactic acidosis. Of those 60 patients, 78.3% had a dose adjustment, with renal impairment, hepatic impairment, surgery and use of radiological contrast media--the risk factors most likely to result in a dose adjustment. When dose adjustments did occur, metformin was withheld on 88.7% of occasions. CONCLUSION: Metformin dose was influenced by the presence of risk factors for lactic acidosis, although it was dependent upon the number and particular risk factor/s present.     

Prevalence and significance of lactic acidosis in diabetic ketoacidosis

Purpose

The prevalence and clinical significance of lactic acidosis in diabetic ketoacidosis (DKA) are understudied. The objective of this study was to determine the prevalence of lactic acidosis in DKA and its association with intensive care unit (ICU) length of stay (LOS) and mortality.

Methods

Retrospective, observational study of patients with DKA presenting to the emergency department of an urban tertiary care hospital between January 2004 and June 2008.

Results

Sixty-eight patients with DKA who presented to the emergency department were included in the analysis. Of 68 patients, 46 (68%) had lactic acidosis (lactate, >2.5 mmol/L), and 27 (40%) of 68 had a high lactate (>4 mmol/L). The median lactate was 3.5 mmol/L (interquartile range, 3.32-4.12). There was no association between lactate and ICU LOS in a multivariable model controlling for Acute Physiology and Chronic Health Evaluation II, glucose, and creatinine. Lactate correlated negatively with blood pressure (r = −0.44; P < .001) and positively with glucose (r = 0.34; P = .004).

Conclusions

Lactic acidosis is more common in DKA than traditionally appreciated and is not associated with increased ICU LOS or mortality. The positive correlation of lactate with glucose raises the possibility that lactic acidosis in DKA may be due not only to hypoperfusion but also to altered glucose metabolism.     

Lactic acidosis and acute ethanol intoxication

Ethanol intoxication has been widely reported as a cause of lactic acidosis. To determine the frequency and severity of ethanol-induced lactic acidosis, patients who presented to an emergency department with a clinical diagnosis of acute ethanol intoxication and a serum ethanol concentration of at least 100 mg/dL were studied. Arterial blood was sampled for lactate and blood gas determinations. A total of 60 patients (mean age, 41 years) were studied. Twenty-two patients sustained minor trauma. Ethanol concentrations ranged from 100 to 667 mg/dL (mean, 287 mg/dL). Lactate concentrations were abnormal (>2.4 mmol/L) in seven patients (11.7%). In all cases, blood lactate was less than 5 mmol/L. Of the patients with elevated lactate, other potential causes for lactic acidosis, including hypoxia, seizures, and hypoperfusion, were also present. Only one case with elevated blood lactate concentration had associated acidemia. Significant elevations of blood lactate are uncommon in acute ethanol intoxication. In patients with ethanol intoxication who are found to have lactic acidosis, other etiologies for the elevated lactate level should be considered.     

Metformin-associated lactic acidosis treated with continuous renal replacement therapy

INTRODUCTION: Lactic acidosis is an infrequent complication of metformin therapy for diabetes mellitus. The presence of clinical conditions, such as renal failure, increases the risk of metformin-associated lactic acidosis (MALA). We present a case of lactic acidosis in a patient with diabetes treated with metformin, complicated by acute renal failure in preexisting chronic nephropathy. CASE SUMMARY: A 70-year-old white male, weighing 77 kg, with diabetes mellitus, coronary heart disease, congestive heart failure (New York Heart Association class III), moderate essential hypertension (stage 2), and renal dysfunction (serum urea, 90 mg/dL; serum creatinine, 1.5 mg/dL; creatinine clearance, 49.8 mL/min/1.73 m2) presented to the emergency department of the General Hospital of Rhodes (Rhodes, Greece), complaining of malaise, respiratory distress, myalgias, disorientation, abdominal discomfort, and increasing somnolence of insidious onset. The patient's regimen included isosorbide mononitrate 60 mg QD, furosemide 40 mg QD, quinapril 20 mg QD, and metformin 850 mg TID. Before this hospitalization, he had received a 2-week course of oral diclofenac sodium 25 mg TID for low back pain. Preliminary laboratory evaluation found leukocytosis (27,300/mm3), severe renal failure (serum urea, 215 mg/dL; serum creatinine, 7.4 mg/dL; calculated creatinine clearance, 10.1 mL/min/1.73 m2), and a high anion gap metabolic acidosis (pH, 6.95; anion gap, 33 mEq/L) in arterial blood gas analysis. His medical and drug history, the clinical and laboratory findings, and the determination of lactate in samples of plasma (7.8 mEq/L), aroused the suspicion of MALA. The Naranjo algorithm scores for metformin and diclofenac sodium were 6 and 7, respectively. The patient received a single session of bicarbonate-buffered continuous venovenous hemodiafiltration (CWHDF) that lasted 16 hours. Ultimately, he was stabilized, and progressive restoration of acid-base balance and renal function was observed. DISCUSSION: We suspect that lactic acidosis may have been related to the use of metformin, the presence of heart and renal failure (contributing to metformin toxicity), and previous use of diclofenac sodium. CVVHDF has an advantage over conventional intermittent hemodialysis in that it corrects acidosis and removes lactate and metformin without risk of hypernatremia or fluid overload. CONCLUSIONS: MALA should be strongly suspected in diabetic patients presenting with high anion gap metabolic acidosis and increased serum lactate level. In the case described, prompt recognition of lactic acidosis and early application of bicarbonate-buffered CVVHDF produced successful results.     

Thiamine deficiency in critically ill patients with sepsis

ObjectiveThe objective of the study was to determine the prevalence of absolute thiamine deficiency (TD) in critically ill patients with sepsis and to examine the association between thiamine levels and lactic acidosis.DesignThis was a prospective, observational study.SettingThe setting was an urban, tertiary care center with approximately 50 000 emergency department visits per year and intensive care units numbering approximately 50 total beds.PatientsThirty study patients admitted with clinical suspicion of infection and evidence of tissue hypoperfusion, as defined by a lactic acid level greater than 4 mmol/L or hypotension (systolic blood pressure <90 mm Hg) requiring vasopressor support, were enrolled. A control group of 30 patients presenting to the emergency department with minor emergencies was also enrolled.InterventionsThere were no interventions.Measurements and Main ResultsPlasma thiamine levels were measured at 0, 24, 48, 72, and 162 hours for patients in the study group. Absolute TD was defined as less than or equal to 9 nmol/L derived from established abnormal ranges per Quest laboratory. In the study group, 3 (10%) of 30 had absolute TD upon presentation; and an additional 3 patients (6/30, 20%) developed TD within 72 hours. None of the 30 controls (0/30, 0%) exhibited absolute TD. Of the vasopressor-dependent population, 7.7% (2/26) displayed TD on presentation. For the group overall, there was no correlation between thiamine and lactic acidosis. However, in patients without liver dysfunction, thiamine was statistically significantly negatively correlated with lactic acidosis (r = ?.50; P = .02). The relationship between thiamine and lactic acidosis held after multivariable regression analysis controlling for age, sex, and comorbid disease (P < .02).ConclusionsThese preliminary findings indicate that critically ill patients may present with TD or develop this deficiency during their acute illness. We also identified a potential association between thiamine levels and lactic acidosis in patients without significant liver injury.     

Metabolic acidosis and coma following a severe acetaminophen overdose

OBJECTIVE: To report a case of metabolic acidosis and coma in a severe acetaminophen overdose. CASE SUMMARY: A 29-year-old white woman was admitted to the emergency department with a diminished level of consciousness and metabolic acidosis. The toxicology screen revealed a serum acetaminophen concentration of 1072 microg/mL, and she was consequently treated with intravenous acetylcysteine. Despite the elevated concentration, the patient did not manifest signs of hepatotoxicity. DISCUSSION: Metabolic acidosis and coma are rare manifestations in acetaminophen overdoses. In published case reports, severe acetaminophen ingestion independently causes metabolic acidosis and coma in the absence of hepatotoxicity. The mechanism by which metabolic acidosis occurs is not clearly defined. Studies conducted on animals demonstrated that in severe overdoses, acetaminophen may cause lactic acidosis by inhibiting mitochondrial respiration. The mechanism by which acetaminophen can cause coma is still unknown. CONCLUSIONS: Severe acetaminophen overdoses can independently cause metabolic acidosis and coma in the absence of hepatotoxicity.     

Delirium and lactic acidosis caused by ethanol and niacin coingestion

A 44-year-old male presented to the emergency department with altered mental status. He was receiving niacin therapy for hypercholesterolemia, and 16 hours earlier had ingested a large quantity of wine. Past medical history was otherwise unremarkable; physical examination revealed paranoid ideation and asterixis. Laboratory evaluation was significant for metabolic acidosis with a calculated anion gap of 39. Liver enzymes were elevated, and lactic acid level was 9.5 mmol/L (normal: 0.5 to 2.2 mmol/L). White blood cell count was 23,100, but all cultures were negative, and all other diagnostic studies, including bilirubin, prothrombin time, and ammonia were normal. The patient recovered rapidly with hydration and administration of thiamine and magnesium. After psychiatric evaluation, a diagnosis of toxic delirium due to niacin and ethanol coingestion was made. This is the first case reporting toxic delirium and lactic acidosis due to niacin and ethanol coingestion. This occurred in the absence of significant hepatic impairment. Possible mechanisms for the observed derangements are discussed.     

Central nervous system toxicity due to mefenamic acid

Mefenamic acid is a fenamate nonsteroidal anti-inflammatory (NSAI) drug, which is used for several years for pain management. However, it has been rarely reported that, mefenamic acid can induce central nervous system toxicity both in toxic doses and therapeutic usage. We report a case of a 27-year-old female who presented to the emergency department (ED) with altered mental status and vomiting. On admission to the ED, she was lethargic and disoriented. Her vital signs were normal and her physical examination was completely normal except dysarthric speech. The etiology of altered mental status was investigated with electrolyte levels, cranial computed tomography, cranial magnetic resonance imaging and EEG, however the results were normal. Her blood gas analysis revealed a deep metabolic acidosis with a pH of 7.14. Neither etiologic agent nor drug use history was provided at the presentation; she had only osteogenesis imperfecta since several years and she had been using various NSAI drugs. However, her relatives later stated that, she took mefenamic acid for her pains since two weeks. After her admission to intensive care unit, her neurologic state was improved gradually after plasmapheresis and she was discharged healthy. Although mefenamic acid has been considered as one of the safe NSAI drugs, its effects due to central nervous system toxicity should be cautiously handled.     

Metformin overdose,but not lactic acidosis <Emphasis Type="Italic">per se</Emphasis>, inhibits oxygen consumption in pigs

ABSTRACT: INTRODUCTION: Hepatic mitochondrial dysfunction may play a critical role in the pathogenesis of metformin-induced lactic acidosis. However, patients with severe metformin intoxication may have a 30-60% decrease in their global oxygen consumption, as for generalized inhibition of mitochondrial respiration. We developed a pig model of severe metformin intoxication to validate this clinical finding and assess mitochondrial function in liver and other tissues. METHODS: Twenty healthy pigs were sedated and mechanically ventilated. Ten were infused with a large dose of metformin (4-8g) and five were not (sham controls). Five others were infused with lactic acid to clarify whether lactic acidosis per se diminishes global oxygen use. Arterial pH, lactatemia, global oxygen consumption (VO2) (metabolic module) and delivery (DO2) (cardiac output by thermodilution) were monitored for 9h. Oxygen extraction was computed as VO2/DO2. Activities of main components of mitochondrial respiratory chain (complex I, II and III, and IV) were measured with spectrophotometry (and expressed relative to citrate synthase activity) in heart, kidney, liver, skeletal muscle and platelets taken at the end of the study. RESULTS: Pigs infused with metformin (6+/-2 g; final serum drug level 77+/-45 mg/L) progressively developed lactic acidosis (final arterial pH 6.93+/-0.24 and lactate 18+/-7 mmol/L, P<0.001 for both). Their VO2 declined over time (from 115+/-34 to 71+/-30 ml/min, P<0.001) despite grossly preserved DO2 (from 269+/-68 to 239+/-51 ml/min, p=0.58). Oxygen extraction accordingly fell from 43+/-10 to 30+/-10 % (P=0.008). None of these changes occurred in either sham controls or pigs infused with lactic acid (final arterial pH 6.86+/-0.16 and lactate 22+/-3 mmol/L). Metformin intoxication was associated with inhibition of complex I in liver (P<0.001), heart (P<0.001), kidney (P=0.003), skeletal muscle (P=0.012) and platelets (P=0.053). The activity of complex II and III diminished in liver (P<0.001), heart (P<0.001) and kidney (P<0.005) while that of complex IV declined in heart (P<0.001). CONCLUSIONS: Metformin intoxication induces lactic acidosis, inhibits global oxygen consumption and causes mitochondrial dysfunction in liver and other tissues. Lactic acidosis per se does not decrease whole-body respiration.     

Etoricoxib-induced life-threatening hyperkalemia and acute kidney dysfunction against the background of telmisartan and a low sodium diet

Drug-induced hyperkalemia is not uncommon and may be life-threatening when presenting acutely in the emergency department. We present a case of severe hyperkalemia precipitated acutely by etoricoxib in a patient who was on telmisartan and a low sodium (potassium chloride-rich) diet. A 75-year-old male with a past medical history of well-controlled diabetes and hypertension was prescribed etoricoxib (90 mg daily) for 3 days for musculoskeletal backache. He had been taking his routine medications including telmisartan and a potassium-rich salt substitute for many years, without any recent change in dosage or quantity. There was evidence of microalbuminurea; however, the renal functions and electrolytes prior to starting etoricoxib were normal. He presented to the emergency department with signs and symptoms of life-threatening hyperkalemia (serum potassium 7.7 mEq/dl), accelerated hypertension, congestive heart failure, pulmonary edema and acute renal failure. Acute medical management and withholding all drugs that could cause hyperkalemia improved his serum potassium levels over 24 h and renal parameters within 5 days. All the other drugs except etoricoxib were restarted under observation over 8 weeks with no recurrence of the acute episode. Non-steroidal analgesics and other COX-2 inhibitors (rofecoxib and celecoxib) have been known to precipitate renal failure and hyperkalemia specially in patients at risk for the same; although not unexpected, this may be the first reported case of life-threatening hyperkalemia precipitated by etoricoxib in a previously stable patient having increased risk of renal failure and hyperkalemia.     

Life-threatening massive empyema: A novel complication of intrathoracic omental herniation

Intrathoracic omental herniation (ITOH) is the herniation of the omentum through the esophageal hiatus without herniation of the stomach. It is a rare disease and serious complications due to ITOH have not been reported in the literature. Here, we reported the case of 47-year old man who presented to the emergency department with dyspnea and chest pain. Enhanced computed tomography (CT) demonstrated a large retrocardiac mass and ITOH was suspected. During the observation period in the emergency department, the patient's condition rapidly deteriorated. Follow-up CT showed large parapneumonic effusion and empyema. Emergency surgery was performed and the omental sac was removed. The patient's vital signs were restored and his symptoms were relieved. He was discharged on hospital day 15 without complications. Emergency physicians should be aware that severe complications of ITOH could develop and that if the patient's symptoms and vital signs worsen, emergency surgery should be considered.     

Colchicine-related death presenting as an unknown case of multiple organ failure

A 45-year-old man presented to the emergency department (ED) with acute renal and hepatic failure as well as hypotension and metabolic acidosis. Despite aggressive intensive care, he had continued hypotension, leukocytosis, fever, renal and hepatic failure, and lactic acidosis. On hospital day 3, pancytopenia was noted. Bone marrow biopsy showed marked aplasia without a specific etiology being elucidated. He received granulocyte colony-stimulating factor and antibiotics, but died on hospital day 12 after a cardiac arrest. The patient repeatedly denied intentional drug ingestion. Due to his clinical course, the poison center recommended obtaining a colchicine level. The plasma colchicine level, 72 h after admission, was 6.1 ng/mL (GC/MS). This level exceeds acute levels reported in some cases of prior fatalities. This case is novel in that the patient’s multiple organ dysfunction remained unexplained for several days before occult colchicine toxicity was implicated as the probable cause by the colchicine level. Also, there was a paucity of gastrointestinal symptoms on presentation, the opposite of what is expected in colchicine toxicity.     

The serotonin syndrome—the need for physician’s awareness

Background

Serotonin syndrome is a potentially life-threatening adverse drug reaction that results from therapeutic drug use, usually of selective serotonin reuptake inhibitors (SSRIs), intentional excessive use or interactions between various drugs.

Case presentation

A 16-year-old Caucasian boy presented to our emergency department (ED) with alteration in his mental status for 6 h prior to arrival. On physical examination in our ED, he was combative and disoriented to time, place and person. He was febrile, hypertensive and tachycardic as well. He had intermittent rigid extremities with myoclonus of both lower extremities. A diagnosis of serotonin syndrome (SS) was made based on history of intake of fluoxetine and clinical signs, which included presence of inducible clonus and agitation. The child received supportive care involving intravenous fluids and intravenous lorazepam. The child was back to his baseline mental status and had a normal neurological exam by 24 h and was discharged home later for follow-up with a psychiatrist.

Conclusions

SS occurs with increasing frequency, and most cases resolve with prompt recognition and supportive care. Failure to make an early diagnosis and to comprehend adverse pharmacological effects of therapy can lead to adverse outcomes.