Resolution of insulin resistance, lactic acidosis, and decrease in mechanical support requirements in patients post orthotopic heart transplant with the use of long-acting insulin glargine.

OBJECTIVE: This study investigates the efficacy of using a long-acting insulin analog, along with the infusion of regular insulin, in achieving appropriate glycemic control and correcting lactic acidosis in patients post orthotopic heart transplant who demonstrate severe lactic acidosis and insulin resistance. METHODS: This was a retrospective study of two cohorts (IRB FLA 20-003) of patients post orthotopic heart transplant with severe lactic acidosis and insulin resistance who were admitted to a tertiary intensive care unit and treated with (group 1) or without long-acting insulin analog (group 2) within the first 24 h of admission to the intensive care unit. Insulin resistance is defined as the requirement for intravenous regular insulin infusion of more than 20 units/h without the ability to achieve appropriate serum glucose level (120-180 mg /dL). Severe lactic acidosis is defined as arterial lactic acid of more than 10 mmol/L. The following parameters were investigated: time to correct lactic acidosis, duration of postoperative mechanical ventilation, the need for periprocedural mechanical circulatory support, and 28-day mortality. RESULTS: The 28-day mortality was zero in both groups. Two patients required periprocedural mechanical support in group one, and ten patients required mechanical support in group two (RR = 0.224, 95%, confidence interval 0.052-0.95, Z = 2.029, p = 0.042). Three patients required tracheostomy in group one, and four patients required tracheostomy in group two (RR 0.84, 95 confidence interval 0.20-3.48, Z = 0.23, P = 0.81). Wilcoxon rank-sum test was used to compare time to correct lactic acidosis, with lactic acid resolution being faster in group one ([Formula: see text]1 = 19.7 h, SD ± 12.6 h [Formula: see text]2 = 29.3 h, SD ± 19.6 h, Z-value - 2.02, p-value 0.043). The duration of mechanical ventilation was less in group one ([Formula: see text]1 = 29 h, SD ± 12.7 h, [Formula: see text]2 = 55.1 h, SD ± 44.5 h, Z-value: - 1.92, p-value 0.05). CONCLUSION: Administration of low-dose long-acting insulin glargine led to the resolution of the lactic acidosis, insulin resistance, and decreased requirements for pressor and inotropic support, which led to decreased need for mechanical circulatory support.

Malignancy Associated Type B Lactic Acidosis: A Rare, yet Fascinating Oncological Emergency.

Type B lactic acidosis has been described infrequently in hematologic malignancies, but even less often in solid tumors. Since 1978, there have been only 58 cases of solid tumor associated Type B lactic acidosis described in the literature. Lung cancer (neuroendocrine) is the most common tumor; others frequently have a poorly/undifferentiated histology. The prognosis is dismal. Malignancy associated type B lactic acidosis is not associated with hypoxemia. The most highlighted pathogenetic mechanism is the Warburg effect (aerobic glycolysis of tumor cells causing excess lactate). We describe a patient with metastatic GI neuroendocrine carcinoma with profound lactic acidosis, who died within 24 hours. When extremely ill cancer patients present with lactic acidosis, sepsis is usually a primary concern. This case highlights the need for providers to consider malignancy associated lactic acidosis (MA-LA) in the differential diagnosis, particularly in patients with advanced malignancies, of lung origin, of neuroendocrine or poorly/undifferentiated histologic subtypes. The implications and approach are distinct from Type A/D lactic acidosis, and would involve treatment of the underlying malignancy at the earliest.

Lactic acidosis in a patient with cancer.

Lactic acidosis is commonly associated with tissue hypoperfusion and gives rise to concern regarding hypoxia or underlying hypotension. In the cancer patient, especially one undergoing chemotherapy, there is always concern for sepsis; however, in the otherwise clincially stable patient with cancer, type B lactic acidosis can also be related to their underlying malignancy. It is considered a haematological emergency given its high mortality rate. However, despite the urgency to treat type B lactic acidosis in these circumstances, treatment options beyond treatment of the malignancy are limited, and its presence portends a poor prognosis. This case highlights our current understanding of type B lactic acidosis and an approach to lactic acidosis evaluation in the cancer patient.

Lactic acidosis after allogeneic haematopoietic stem cell transplantation potentially related to letermovir.

A 53-year-old woman with a history of acute myeloid leukaemia received a second allogeneic haematopoietic stem cell transplant and was prescribed, among other medications, acyclovir and letermovir (480-mg daily oral dose) for prophylaxis of, respectively, herpes simplex and cytomegalovirus infection. The patient was admitted in the intensive care unit for dyspnoea and oliguria. Laboratory investigations revealed acute kidney injury but also a severe and progressive lactic acidosis. Liver function tests were within normal range. The combination of lactic acidosis, hypoglycaemia and acylcarnitine profile in plasma raised the suspicion of mitochondrial toxicity. Letermovir therapy was interrupted, and determination of plasma letermovir pharmacokinetics revealed a prolonged terminal half-life (38.7 h) that was not significantly influenced by continuous venovenous haemofiltration. Exploration for genetic polymorphisms revealed that the patient was SLCO1B1*5/*15 (c.521T>C homozygous carrier and c.388A>G heterozygous carrier) with a predicted nonfunctional organic anion transporting polypeptide 1B1 protein. The relationship between letermovir accumulation and development of lactic acidosis requires further observations.

Continuous veno-venous hemodiafiltration in metformin-associated lactic acidosis caused by a suicide attempt: A report of two cases.

Lactic acidosis is the most important and life-threatening side effect of metformin that is widely used in the treatment of type 2 diabetes mellitus. In this case report, two cases who were treated in our intensive care unit for lactic acidosis due to high-dose metformin intake for suicidal purposes are presented. The first patient could be successfully treated with continuous venous-venous hemodiafiltration (CVVHDF) and supportive therapy. The second case required endotracheal intubation and mechanical ventilation in addition to CVVHDF and supportive therapy due to delay in treatment.

Spurious point-of-care lactate elevation in ethylene glycol intoxication: rediscovering a clinical pearl.

A 76-year-old man was found unresponsive and brought to the emergency department. Initial workup showed profound lactic acidosis on a point-of-care arterial blood gas, without clinical signs of hypoperfusion. Investigations for types A and B lactic acidosis revealed no unifying diagnosis to explain both his altered mental status and profound lactic acidosis. A toxicology workup revealed an increased osmolar gap and an elevated ethylene glycol level. The lactic acidosis and his mental status completely normalised within 8 hours of renal replacement therapy initiation and fomepizole administration. Ethylene glycol metabolites have similar molecular structure with L-lactate. Some blood gas analysers are unable to differentiate them, resulting in an artefactual lactate elevation. Our case highlights the importance of recognising a falsely elevated lactate, which should raise clinical suspicion of ethylene glycol poisoning, as the treatment is time-sensitive to prevent complications and mortality.

Metformin, chronic nephropathy and lactic acidosis: a multi-faceted issue for the nephrologist.

Metformin is currently considered a first-line therapy in type 2 diabetic patients. After issuing warnings for decades about the risks of lactic acidosis in patients with chronic nephropathy, metformin is now being re-evaluated. The most recent evidence from the literature has demonstrated both a low, acceptable risk of lactic acidosis and a series of favorable effects, which go beyond its hypoglycemic activity. Patients treated with metformin show a significant mortality reduction and lower progression towards end-stage renal disease in comparison with those treated with other hypoglycemic drugs. Concerning lactic acidosis, in the last few years it has been shown how lactic acidosis almost always developed when patients kept taking the drug in the face of a concomitant disease or situation such as sepsis, fever, diarrhea, vomiting, which reduced metformin renal clearance. Actually, clearance of metformin is mainly renal, both by glomerular filtration and tubular secretion (apparent clearance 933-1317 ml/min, half-life < 3 h). As regards treatment, in cases of lactic acidosis complicated by acute kidney injury, continuous renal replacement therapy (CRRT) plays a crucial role. Besides the elimination of metformin, CRRT  improves survival by correcting acidosis, electrolyte alterations, and maintaining fluid balance. Lactic acidosis almost always develops because of preventable drug accumulation. Therefore, prevention is a key factor. Patients should be aware that discontinuation for a limited time does not affect their health, even when it may be inappropriate, but it may avoid a serious, potentially fatal adverse event.

Lactic Acidosis Secondary to Thiamin Deficiency Following Autologous Stem Cell Transplantation.

A 22-month-old female with high-risk neuroblastoma completed 5 cycles of chemotherapy then underwent high-dose chemotherapy with autologous stem cell rescue (ASCR). Parenteral nutrition was administered from day +2 following ASCR, as she was unable to tolerate nasogastric feeds because of grade IV mucositis and vomiting. On day +12, she developed worsening metabolic acidosis with above reportable levels of lactic acid. Given the patient's well clinical appearance and paucity of evidence of end-organ dysfunction on physical examination and on laboratory studies, there was high suspicion that the patient's lactic acidosis did not result from tissue hypoxia and was, in fact, a type B lactic acidosis. Thiamin was empirically administered, with rapid improvement in lactic acidosis. Thiamin deficiency was later confirmed by laboratory studies drawn prior to thiamin administration.

Life-threatening lactic acidosis occurring in adults with mitochondrial disorders.

Although relatively common in children, severe acute lactic acidosis is rare in adults with mitochondrial myopathies. We report here three cases, aged 27, 32 and 32 years, who developed life-threatening metabolic crisis with severe lactic acidosis, requiring hospitalisation in intensive care unit. Plasma lactates were elevated 10 to 15 fold normal values, necessitating extra-renal dialysis. By contrast CK levels were moderately increased (3 to 5N). No triggering factor was identified, but retrospectively all patients reported long-lasting mild muscle fatigability and weakness before their acute metabolic crisis. All of them recovered after prolonged intensive care but resting lactate levels remained elevated. Muscle biopsy showed ragged-red and COX-negative fibers in two patients and mild lipidosis in the third one. Heteroplasmic pathogenic point mutations were detected in MT-TL1 (m.3280G>A;m.3258C>T) and MT-TK (m.8363A>G). Life-threatening lactic acidosis may thus be a major inaugural clinical manifestation in adults with mitochondrial myopathies. Prolonged intensive care may lead to a dramatic and sustained improvement and is mandatory in such cases.

Targeting acidity in cancer and diabetes.

While cancer is commonly described as "a disease of the genes", it is also a disease of metabolism. Indeed, carcinogenesis and malignancy are highly associated with metabolic re-programming, and there is clinical evidence that interrupting a cancer's metabolic program can improve patients' outcomes. Notably, many of the metabolic adaptations observed in cancer are similar to the same perturbations observed in diabetic patients. For example, metformin is commonly used to reduce hyperglycemia in diabetic patients, and has been demonstrated to reduce cancer incidence. Treatment with PI3K inhibitors can induce hyperinsulinemia, which can blunt therapeutic efficacy if unchecked. While commonalities between metabolism in cancer and diabetes have been extensively reviewed, here we examine a less explored and emergent convergence between diabetic and cancer metabolism: the generation of lactic acid and subsequent acidification of the surrounding microenvironment. Extracellular lactic acidosis is integral in disease manifestation and is a negative prognostic in both disease states. In tumors, this results in important sequela for cancer progression including increased invasion and metastasis, as well as inhibition of immune surveillance. In diabetes, acidosis impacts the ability of insulin to bind to its receptor, leading to peripheral resistance and an exacerbation of symptoms. Thus, acidosis may be a relevant therapeutic target, and we describe three approaches for targeting: buffers, nanomedicine, and proton pump inhibitors.

Effect of high-flow high-volume-intermittent hemodiafiltration on metformin-associated lactic acidosis with circulatory failure: a case report.

BACKGROUND: Metformin-associated lactic acidosis is a well-known life-threatening complication of metformin. We here report the case of a patient who developed metformin-associated lactic acidosis without organ manifestations, due to the simultaneous ingestion of an overdose of metformin and alcohol, and who recovered with high-flow high-volume intermittent hemodiafiltration. CASE PRESENTATION: A 44-year-old Asian woman with type 2 diabetes attempted suicide by ingesting 10 tablets of metformin 500 mg and drinking approximately 600 mL of Japanese sake containing 15% alcohol. She was transferred to our emergency department because of disturbed consciousness. Continuous intravenous administration of noradrenalin (0.13 µg/kg per minute) was given because she was in shock. Laboratory findings included a lactate level of 119 mg/dL (13.2 mmol/L), bicarbonate of 14.5 mmol/L, and serum metformin concentration of 1138 ng/mL. She was diagnosed as having metformin-associated lactic acidosis worsened by alcohol. After 4560 mL of bicarbonate ringer (Na+ 135 mEq/L, K+ 4 mEq/L, Cl- 113 mEq/L, HCO3- 25 mEq/L) was administered, high-flow high-volume intermittent hemodiafiltration. (dialysate flow rate: 500 mL/min, substitution flow rate: 3.6 L/h) was carried out for 6 h to treat metabolic acidosis and remove lactic acid and metformin. Consequently, serum metformin concentration decreased to 136 ng/mL and noradrenalin administration became unnecessary to maintain normal vital signs. On hospital day 12, she was moved to the psychiatry ward. CONCLUSIONS: HFHV-iHDF may be able to remove metformin and lactic acid efficiently and may improve the condition of hemodynamically unstable patients with metformin-associated lactic acidosis.

Lactic Acidosis in a Critically Ill Patient: Not Always Sepsis.

Lactic acidosis in the emergency department and other hospital settings is typically due to tissue hypoxia with sepsis being the most common cause. However, in patients with persistently elevated lactate without evidence of inadequate oxygen delivery, type B lactic acidosis should be considered. We report the case of a 12-year-old boy with relapsed and refractory pre-B-cell acute lymphoblastic leukemia who presented in distress with tachycardia, history of fever, and diffuse abdominal tenderness. The patient had severe metabolic acidosis with elevated lactate upon arrival to the emergency department. Despite aggressive fluid resuscitation and intravenous antibiotics, the patient's acidosis worsened. Serial blood cultures were negative, and he was eventually diagnosed with type B lactic acidosis secondary to relapsed acute lymphoblastic leukemia.

Recurrent hypoglycemia secondary to metformin toxicity in the absence of co-ingestions: a case report.

BACKGROUND: Metformin toxicity is well known to cause lactic acidosis. Multiple cases of hypoglycemia due to isolated metformin overdose have been reported. Increased glucose consumption secondary to anaerobic metabolism has been reported as a possible explanation. CASE PRESENTATION: A 23-year-old Arabic woman took 30 g of metformin. In the emergency department, 4 hours after of the event, she was fatigued but vitally stable. During her hospitalization, she had severe lactic acidosis, hypotension corrected with fluid boluses and vasopressors, and multiple episodes of hypoglycemia (6.3 mg/dL, 38 mg/dL, and 42 mg/dL), requiring multiple 50% dextrose-water boluses. The three hypoglycemic episodes occurred coincident with severe lactic acidosis. She improved after 24 hours of continuous renal replacement therapy. CONCLUSIONS: Hypoglycemia can be induced by metformin toxicity in the absence of co-ingestants. A possible explanation of metformin-induced hypoglycemia is increased glucose consumption due to anaerobic metabolism, decreased oral intake, decreased liver glucose production, and decreased glucose absorption.

Lessons learnt from managing a case of dengue hemorrhagic fever complicated with acute liver failure and acute kidney injury: a case report.

BACKGROUND: Dengue is a common arboviral infection with a diverse spectrum of clinical manifestations. Dengue hemorrhagic fever is a more severe form of infection characterized by plasma leak and hemoconcentration. Although hepatic dysfunction is common in dengue illness, massive liver necrosis is rarely reported. Lactic acidosis is a poor prognostic marker in liver failure related to dengue. Management of acute renal injury in dengue hemorrhagic fever due to prolonged shock is challenging as the fluid reabsorption during the recovery phase expands the intravascular volume and precipitates heart failure and pulmonary edema. CASE PRESENTATION: We report the case of a 43-year-old Sri Lankan Sinhalese woman with serologically confirmed dengue fever presenting with evidence of plasma leakage developing acute liver failure evidenced by deranged liver functions, coagulopathy, and altered sensorium and acute kidney injury with anuria. She had elevated serum lactate levels. In addition to the "standard care," she was managed with intravenously administered N-acetyl cysteine and blood transfusions, even in the absence of bleeding or dropping packed cell volume, targeting a higher packed cell volume anticipating a better oxygenation at tissue level. Continuous veno-venous hemodialysis was employed and continued for 138 hours removing the fluids reabsorbed during the recovery phase to prevent her from developing heart failure and pulmonary edema. She made full recovery with no sequelae. CONCLUSIONS: N-acetyl cysteine and packed cell transfusion aiming at a higher packed cell volume to maintain adequate tissue perfusion during shock may be beneficial in acute liver failure due to dengue virus. The use of a continuous form of renal replacement such as continuous veno-venous hemodialysis is of paramount importance in managing fluid states in the recovery phase of dengue hemorrhagic fever in those with renal impairment. Interesting observations made in the fluid dynamics during the reabsorption phase need further studies preferably with an animal model.

Importância da transfaunação no tratamento da acidose láctica ruminal aguda induzida em cabras e ovelhas / Value of transfaunation for the treatment of induced ruminal lactic acidosis in goats and sheep

O objetivo deste trabalho foi avaliar a importância da transfaunação no tratamento e recuperação de cabras e ovelhas com acidose lática ruminal aguda (ALRA) induzida experimentalmente. Seis cabras (41,2±5,6kg) e seis ovelhas (46,8±4,57kg), não gestantes e não lactantes, receberam 15g de sacarose por quilo de peso corporal para indução da enfermidade. A ALRA foi induzida duas vezes em cada animal, com intervalo de 30 dias após recuperação total da primeira indução. Os procedimentos terapêuticos consistiram na remoção do conteúdo ruminal líquido por lavagem e sifonamento com auxílio de sondagem esofágica, e na correção da acidose metabólica com soluções eletrolíticas, contendo lactato ou bicarbonato de sódio, infundidas por via intravenosa. A transfaunação fez parte de apenas um dos tratamentos de cada animal e consistiu na administração por sondagem esofágica de 2L de suco ruminal de um bovino sadio. A recuperação completa foi avaliada por exames físicos e exames do suco ruminal realizados até quatro dias após os procedimentos terapêuticos. A eficácia dos protocolos de tratamento, com ou sem transfaunação, foi comparada. O protocolo de indução foi efetivo em induzir a enfermidade e as cabras e ovelhas apresentaram sinais clínicos de intensidade máxima (apatia, atonia ruminal, distensão abdominal, diarreia de consistência pastosa a líquida e desidratação moderada) 16 horas após a administração intrarruminal de sacarose, sem distinção entre as espécies. Neste momento, as características do suco ruminal mostraram-se semelhantes aos quadros típicos de ALRA. A frequência de movimentos ruminais se normalizou no terceiro dia após os procedimentos terapêuticos, sem diferença entre as espécies, e independente de terem recebido a transfaunação ou não. A transferência de suco ruminal também não acelerou a recuperação do apetite, que foi considerado normal somente no quarto dia após os procedimentos terapêuticos, em ambas as espécies. Em relação ao líquido ruminal, quando receberam a transfaunação, os caprinos e ovinos apresentaram recuperação das características de cor, odor e consistência mais rapidamente do que quando não receberam. A atividade fermentativa da microbiota ruminal não sofreu influência da transfaunação e se normalizou dois e três dias após os procedimentos terapêuticos nas ovelhas e cabras, respectivamente. A transfaunação promoveu o retorno mais rápido da população de protozoários ruminais, que já foram observados 24 horas após os procedimentos terapêuticos, em ambas as espécies. Quando os animais não receberam a transfaunação, o retorno dos protozoários só ocorreu no segundo dia após os procedimentos terapêuticos. A recuperação completa dos animais estudados ocorreu em até quatro dias, independente da realização da transfaunação ou não. Conclui-se que a transferência de suco ruminal não pode ser considerada medida crucial para o tratamento e convalescença de caprinos e ovinos acometidos por de ALRA.(AU)

The aim of this study was to evaluate the value of transfaunation in the treatment and recovery of goats and sheep with acute rumen lactic acidosis (ARLA) experimentally induced. Six goats (41.2±5.6kg) and six sheep (46.8±4.57kg), non-pregnant and non-lactating, received 15g of sucrose per kilogram of body weight for the disease induction. The ARLA was induced in each animal twice with an interval of 30 days after full recovery of the first induction. Therapeutic procedures consisted in removal of the rumen fluid content by washing and siphoning with an esophageal tube and correction of metabolic acidosis with intravenous electrolyte solutions containing sodium lactate or sodium bicarbonate. The transfaunation was part of only one of each animal treatment and consisted in administration of two liters of rumen fluid colleted from a healthy cow. Complete recovery was assessed by physical examinations and rumen fluid examinations up to four days after therapeutic procedures. The efficacy of treatment protocols, with or without transfaunation was compared. The protocol used was effective in induce the disease and goats and sheep showed clinical signs of maximum intensity (apathy, rumen stasis, abdominal distension, diarrhea and moderate dehydration) 16 hours after the intraruminal administration of sucrose. At this moment, the characteristics of ruminal fluid were similar to the typical ARLA. The frequency of ruminal movements became normal on the third day after therapeutic procedures, with no difference between species, and regardless transfaunation. The ruminal fluid transfer did not accelerate the recovery of appetite, considered normal only on the fourth day after treatment in both species. When transfauntation was received, goats and sheep showed recovery of characteristics of color, odor and consistency faster than when they did not receive. The fermentative activity of the rumen microbiota was not impacted by transfaunation and normalized two and three days after therapeutic procedures in sheep and goats, respectively. The transfaunation promoted faster return of the protozoa population, which was observed 24 hours after therapeutic procedures in both species. When the animals did not receive transfaunation, the protozoa returns occurred only on the second day after therapeutic procedures. Full recovery of the animals occurred within four days, regardless of transfaunation. In conclusion, the ruminal fluid transfer can not be considered crucial for the treatment and convalescence of goats and sheep affected by ARLA.(AU)

Extra-Renal Indications for Continuous Renal Replacement Therapy.

Continuous renal replacement therapy (CRRT) has many potential indications that extend beyond the traditional removal of uremic waste products. Many of these stem from the capacity of CRRT to remove middle-sized molecules and its suitability for haemodynamically unstable patients. Using CRRT for immunomodulation to remove circulating plasma cytokines has created great enthusiasm and, in the past, immunomodulation was a frequently reported indication for commencing CRRT. Unfortunately, recent evidence from randomized controlled trials has been discouraging, and CRRT cannot be recommended for immunomodulation. The contemporary indications of CRRT include fluid removal in fluid overloaded patients with poor tolerance of volume load when other means of fluid removal are insufficient or have failed; removal of toxins such as ammonia and myoglobin, as well as acidosis management in metformin-associated lactic acidosis when severe acid-base disorders coexist. Other potential indications include removal of ingested toxins and tumour lysis syndrome in severely unstable critically ill patients.

Peripheral venoarterial extracorporeal membrane oxygenation for severe hyperlactataemia after cardiac surgery: a pilot study.

BACKGROUND: Severe hyperlactataemia in patients after cardiac surgery is associated with poor prognosis and implies possible splanchnic hypoperfusion. Peripheral venoarterial extracorporeal membrane oxygenation (splanchnic ECMO) may be more effective at reducing lactic acidosis for these patients. OBJECTIVE: To investigate whether splanchnic ECMO attenuates hyperlactataemia and liver enzyme release in these patients, despite them having a cardiac index > 2 L/min/m2 and a mixed venous oxygen saturation > 55%. DESIGN AND PARTICIPANTS: Retrospective matched case- control study of patients treated with splanchnic ECMO for hyperlactataemia. Seven patients who had had cardiac surgery were treated with splanchnic ECMO compared with seven matched control patients. RESULTS: We observed a mean decrease in lactate levels from 9.9 mmol/L (SD, 2.9 mmol/L) to 1.4 mmol/L (SD, 0.6 mmol/L) in patients receiving 48 hours of splanchnic ECMO, compared with a mean of 10.4 mmol/L (SD, 2.8 mmol/L) to 4.4 mmol/L (SD, 5 mmol/L) during 48 hours in control patients (P < 0.0001). Normalisation of lactate levels (to < 2 mmol/L) was achieved within a mean of 16.3 hours (SD, 14.6 hours) with splanchnic ECMO, compared with 38.3 hours (SD, 23.8 hours) in the control group (P = 0.029). The median increase in alanine aminotransferase level with splanchnic ECMO was 68% (range, -84% to 2015%) compared with 158% (range: 0%-6024%) (not significant) in control patients. CONCLUSION: In a selected cohort of patients who had had cardiac surgery with severe post-operative hyperlactataemia, despite an acceptable cardiac index and a mixed venous oxygen saturation, splanchnic ECMO appeared to reduce overall lactate levels and time to normalisation of lactataemia.