[The 475th case: renal tubular acidosis, renal failure, anemia, and lactic acidosis].

A 47-year-old female patient presented nausea and vomiting for half a year and elevated serum creatinine for 3 days. Proximal renal tubular acidosis (RTA) complicated with anemiawas confirmed after admission. Secondary factors, such as autoimmune disease, drugs, poison, monoclonal gammopathy, were excluded. Renal biopsy revealed acute interstitial nephritis. The patient was administrated with daily prednisone 50 mg, sodium bicarbonate 4 g, 3 times per day, erythropoietin 3 000 U, 2 times per week, combined with potassium, calcium, and calcitriol tablets. Serum creatinine reduced to 90 µmol/L. However nausea and vomiting deteriorated with lactic acidosis. Bone marrow biopsy indicated the diagnosis of non-Hodgkin lymphoma, therefore the patient was treated with chemotherapy. Although metabolic acidosis improved gradually after chemotherapy, severe pneumocystis carinii pneumonia developed two weeks later. The patient refused further treatment and was discharged.

Case of acute hepatic injury and elevated ethanol levels in a non-alcoholic adult.

Blood ethanol concentration is measured using different techniques. Gas chromatography/mass spectrometry is used in forensic laboratories to measure whole blood ethanol levels while enzyme immunoassay is often used in hospitals to measure serum or plasma ethanol levels. Lactic acidosis can theoretically cause false elevation of blood ethanol levels measured through enzymatic assay because this method measures the reduction of nicotinamide adenine dinucleotide (NAD+) to nicotinamide adenine dinucleotide- hydrogen (NADH) via the action of a dehydrogenase. Here, we present a rare incidence of ethanol level elevation in a non-alcoholic adult male secondary to lactic acidosis from a rare form of large B-cell lymphoma with infiltration of the liver.

Metformin-Associated Lactic Acidosis Presenting Like Acute Mesenteric Ischemia.

BACKGROUND: Metformin-associated lactic acidosis is a rare but serious complication of taking metformin. Making the diagnosis in the emergency department requires vigilance because the presentation can mimic other diseases. CASE REPORT: We present a case of a patient with diabetes who presented moribund with symptoms and signs consistent with mesenteric ischemia. This diagnosis was seemingly confirmed through computed tomography, and as a result the patient was brought to surgery for emergent exploratory laparotomy. Our patient made a remarkable recovery upon initiation of hemodialysis, demonstrating the need to initiate this life-saving procedure early. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Metformin levels are rarely available in the setting of the emergency department. Clinicians must remain alert, recognize that imaging studies may be misleading, and consider hemodialysis early in addition to surgical interventions.

Lactic acidosis due to metformin in type 2 diabetes mellitus and chronic kidney disease stage 3-5: is it significant?

PURPOSE: To study the incidence of lactic acidosis due to metformin in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) stage 3-5. METHODS: We estimated plasma lactate in patients of CKD stage 3 and worse who were continuing metformin on their own prior to stopping the drug. RESULT: Of 40 patients included, median duration of T2DM was 60 months (interquartile range IQR 24-120). The mean serum creatinine was 309.4 ± 159.1 µmol/L and mean eGFR was 27.82 ± 12.93 mL/min/1.73 m2 with 3 (7.5%), 16 (40%), 11 (27.5%) and 10 (25%) in CKD stages 3a, 3b, 4 and 5, respectively. They were receiving metformin for a median duration of 24 months (IQR 12.5-60), an average dose of 896 ± 350 mg per day. The median of plasma lactate was 1.36 mmol/L (IQR 1.11-1.75 mmol/L) with three (7.5%) having levels above normal, two (20%) in CKD stage 5 and one (9.1%) in stage 4. CONCLUSION: Metformin can be safely used in CKD stage 3 and with regular measurement of plasma lactate in later stages.

Nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock.

Hemorrhagic shock depletes nicotinamide adenine dinucleotide (NAD) and causes metabolic derangements that, in severe cases, cannot be overcome, even after restoration of blood volume and pressure. However, current strategies to treat acute blood loss do not target cellular metabolism. We hypothesized that supplemental nicotinamide mononucleotide (NMN), the immediate biosynthetic precursor to NAD, would support cellular energetics and enhance physiologic resilience to hemorrhagic shock. In a rodent model of decompensated hemorrhagic shock, rats receiving NMN displayed significantly reduced lactic acidosis and serum IL-6 levels, two strong predictors of mortality in human patients. In both livers and kidneys, NMN increased NAD levels and prevented mitochondrial dysfunction. Moreover, NMN preserved mitochondrial function in isolated hepatocytes cocultured with proinflammatory cytokines, indicating a cell-autonomous protective effect that is independent from the reduction in circulating IL-6. In kidneys, but not in livers, NMN was sufficient to prevent ATP loss following shock and resuscitation. Overall, NMN increased the time animals could sustain severe shock before requiring resuscitation by nearly 25% and significantly improved survival after resuscitation (P = 0.018), whether NMN was given as a pretreatment or only as an adjunct during resuscitation. Thus, we demonstrate that NMN substantially mitigates inflammation, improves cellular metabolism, and promotes survival following hemorrhagic shock.

Involvement of organic cation transporter 2 in the metformin-associated increased lactate levels caused by contrast-induced nephropathy.

The application of iodinated contrast medium has become a risk factor for metformin-associated lactic acidosis (MALA), which leads to the accumulation of metformin in vivo is one of the principal reasons for MALA. However, the molecular mechanism of the adverse event is not yet clear. In this study, iohexol injection was used as a model drug. The contrast agent acute kidney injury rat model, in vivo rat pharmacokinetic study, kidney slices and HK-2 cells were performed to elucidate the pharmacokinetic molecular mechanism of accumulation of metformin caused by contrast-induced nephropathy (CIN). Plasma exposure of metformin was increased significantly in the CIN group compared with that in the normal and control groups. The AUC of metformin was from 2791 ±â€¯382 µg min mL-1 to 4784 ±â€¯767 µg min mL-1. The cumulative urinary excretion of metformin was also reduced in the CIN group. The uptake of metformin decreased in kidney slices in the CIN group. Compared with the normal and control groups, the blood lactate concentration was increased after intravenous administration of metformin in the CIN group followed a similar trend to the plasma concentrations of metformin. After treatment with contrast medium, the expression of OCT2 was reduced in rat kidney and HK-2 cells. These findings highlight that OCT2 deficiency was associated with increased lactate levels during metformin treatment caused by CIN.

Type B lactic acidosis, an uncommon paraneoplastic syndrome.

A 67-year-old male presented with anasarca and persistent non-pruritic rash of lower extremities. Physical examination was positive for subcutaneous edema with a non-blanching rash of abdomen and lower extremities. Labs showed leukocytosis, lymphocytosis, anemia and thrombocytopenia. He also had acute kidney injury and high anion gap (AG) metabolic acidosis with elevated lactic acid (11.3 mg/dL). Computerized tomography (CT) of abdomen and pelvis showed hepatosplenomegaly, ascites and abdominal lymphadenopathy. Peripheral blood (PB) smear showed blastiod appearing lymphocytes. He was started on bicarbonate infusion due to persistent lactic acidosis (LA), however showed no significant improvement. He was started on IV dexamethasone on 3rd day of hospitalization based on preliminary result of peripheral picture which led to some improvement in LA. Following the confirmation of mantle cell lymphoma (MCL) on bone marrow (BM) biopsy and immunophenotyping, the patient started receiving VR-CAP regimen (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) which led to significant improvement in LA and leukocytosis. After discharge, he received further chemotherapy with resolution of the LA and normalization of blood counts. Restaging tests confirmed a complete remission with resolution of the skin rash, resolution of the pathological lymphadenopathy and hepatosplenomegaly on imaging, and absence of lymphoma on a repeat BM biopsy.

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.

Lactate serum concentrations during treatment with nucleos(t)ide analogues in hepatitis B with or without cirrhosis.

OBJECTIVE: The aim of this study is to evaluate the clinical implications of lactate concentrations in patients with hepatitis B with or without cirrhosis during treatment with nucleos(t)ide analogues. PATIENTS AND METHODS: One hundred and seven consecutive patients with chronic hepatitis B and median age 57 (24-85) years were prospectively included. Lactate concentrations were measured at baseline and at 12, 24, 36, 48, and 60 months following the baseline measurements. Eight (n=8, 7.5%) patients received lamivudine, 38 (n=38, 35.5%) patients received tenofovir, 34 (n=34, 31.8%) patients received entecavir, and 27 (n=27, 25.2%) patients received combined therapy. RESULTS: None of the patients developed lactic acidosis during follow-up [median: 58 (6-155) months]. Overall, no trends of the lactic acid evolution were observed over time; however, there was a nonsignificant increasing trend in patients with cirrhosis up to 24 months of treatment. This increasing trend was significant in female patients with cirrhosis (P=0.016). The age of the patients, the presence of cirrhosis, and hepatocellular carcinoma were strongly associated with the survival of all patients. In the group of cirrhotic patients, the only independent prognostic factor that was associated with patients' survival was the Child-Pugh class. CONCLUSION: None of the patients developed lactic acidosis. There is an indication of an increasing trend of lactic acid levels up to 24 months of therapy in female cirrhotic patients.

Hyperlactatemia and Cardiac Surgery.

The normal blood lactate level is 0-2 mmol/L, and a value above 3-5 mmol/L is variably used to define hyperlactatemia. In cardiac surgical patients, hyperlactatemia can arise from both hypoxic and non-hypoxic mechanisms. The major non-hypoxic mechanism is likely stress-induced accelerated aerobic metabolism, in which elevated lactate results from a mass effect on the lactate/pyruvate equilibrium. The lactate/pyruvate ratio is normal (<20) in this circumstance. Hyperlactatemia can also result from impaired global or regional oxygen delivery, in which case the lactate/pyruvate ratio is typically elevated (>20). Lactate is a strong anion that is virtually fully dissociated at physiological pH. As such, increased lactate concentration reduces the strong ion difference and exerts an acidifying effect on the blood. Hyperlactatemia in cardiac surgery patients has been categorized as either early or late onset. Early-onset hyperlactatemia is that which develops in the operating room or very early following intensive care unit (ICU) admission. Early-onset hyperlactatemia is strongly associated with adverse outcome and probably arises as a consequence of both hypoxic (e.g., microcirculatory shock) and non-hypoxic (accelerated aerobic metabolism) mechanisms. By contrast, late-onset hyperlactatemia is a benign, self-limiting condition that typically arises within 6-12 hours of ICU admission and spontaneously resolves within 24 hours. Late onset hyperlactatemia occurs in the absence of any evidence of global or regional tissue hypoxia. The mechanism of late onset hyperlactatemia is not understood. Hyperlactatemia is a common accompaniment to treatment with ß2-agonists such as epinephrine. Epinephrine-induced hyperlactatemia is thought to be due to accelerated aerobic metabolism and requires no specific intervention. Irrespective of the cause, the presence of hyperlactatemia should trigger a search for remedial causes of impaired tissue oxygenation, bearing in mind that normal-or even supranormal-indices of global oxygen delivery may exist despite regional tissue hypoperfusion.

Intraoperative acidosis is a new predictor for postoperative pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND: Early diagnosis of postoperative pancreatic fistula (POPF) is important for proper interventions. The preoperative, intraoperative and early postoperative biochemical markers have predictive value of POPF. The present study was to evaluate several simple biochemical parameters in the prediction of POPF. METHODS: Patients who underwent pancreaticoduodenectomy in our center between 2006 and 2015 were reviewed retrospectively. Preoperative and early postoperative biochemical parameters were evaluated. Additionally, the relationship between POPF and pH and lactate level at the end of surgery were analyzed, and neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and red cell distribution width-to-platelet ratio (RPR) were calculated for postoperative days (PODs) 1 and 3. Diagnosis and grading of POPF were performed according to the standards of the International Study Group on Pancreatic Fistula. The patients were divided into two groups: Group 1 with no fistula or grade-A fistula; group 2 with grade-B or -C fistula. These simple biochemical markers were then compared between the two groups. RESULTS: Serum amylase level was significantly higher at POD3, and pH level was significantly lower at the end of operation in group 2 compared with those in group 1. However, the serum amylase was below the upper limit of normal serum level and therefore, the difference was not significant in clinical practice. Receiver operating charecteristic curve analysis showed that pH level was a reliable predictor of POPF (area under the curve: 0.713; 95% CI: 0.573-0.853). CONCLUSIONS: A low pH level at the end of pancreaticoduodenectomy was a risk factor of POPF. NLR, PLR, and RPR had no predictive value of POPF after pancreaticoduodenectomy.

Cost effectiveness of universal umbilical cord blood gas and lactate analysis in a tertiary level maternity unit.

OBJECTIVE: There is an increasing body of literature supporting universal umbilical cord blood gas analysis (UCBGA) into all maternity units. A significant impediment to UCBGA's introduction is the perceived expense of the introduction and associated ongoing costs. Consequently, this study set out to conduct the first cost-effectiveness analysis of introducing universal UCBGA. METHODS: Analysis was based on 42,100 consecutive deliveries ≥23 weeks of gestation at a single tertiary obstetric unit. Within 4 years of UCBGA's introduction there was a 45% reduction in term special care nursery (SCN) admissions >2499 g. Incurred costs included initial and ongoing costs associated with universal UCBGA. Averted costs were based on local diagnosis-related grouping costs for reduction in term SCN admissions. Incremental cost-effectiveness ratio (ICER) and sensitivity analysis results were reported. RESULTS: Under the base-case scenario, the adoption of universal UCBGA was less costly and more effective than selective UCBGA over 4 years and resulted in saving of AU$641,532 while adverting 376 SCN admissions. Sensitivity analysis showed that UCBGA was cost-effective in 51.8%, 83.3%, 99.6% and 100% of simulations in years 1, 2, 3 and 4. These conclusions were not sensitive to wide, clinically possible variations in parameter values for neonatal intensive care unit and SCN admissions, magnitude of averted SCN admissions, cumulative delivery numbers, and SCN admission costs. CONCLUSIONS: Universal UCBGA is associated with significant initial and ongoing costs; however, potential averted costs (due to reduced SCN admissions) exceed incurred costs in most scenarios.

Perioperative considerations in adult mitochondrial disease: A case series and a review of 111 cases.

Mitochondrial disease has been uncommon conditions, still results in death during childhood in many cases. The ideal anesthetic pharmacological management strategy for adult patients with mitochondrial disease is currently unclear. In this study, we presented features of the anesthesia methods employed and the perioperative complications of patients in our institution and in previously published case reports. We report the use of general anesthesia 7 times in 6 adult patients with mitochondrial disease during 2004-2014. All cases were performed with maintained intravenous anesthesia. One case was reintubated on the day after surgery, but the cause of death was not directly related to anesthesia. One hundred and eleven general anesthesia cases in 97 adult patients with mitochondrial disease were described in 83 the literature. Although several severe perioperative complications and deaths have been reported, malignant hyperthermia had not been reported in adult cases, and metabolic disorder called propofol infusion syndrome had also not been reported in adult patients undergone total intravenous anesthesia. Perioperative complications of lactic acidosis were reported more in inhalation anesthesia than intravenous anesthesia. Therefore we recommended intravenous anesthesia rather than inhalation anesthesia for adult mitochondrial disease.

Utility of the shock index in patients with sepsis.

The shock index (SI) equals the heart rate/systolic blood pressure and has been used to predict clinical outcomes, especially in trauma and surgery patients. The authors reviewed the literature to determine its utility in the management of patients with sepsis and in the prediction of adverse outcomes in these patients. The medical literature was searched using PubMed, Scopus, Web of Science and Google Scholar databases to identify articles in English on the SI in humans. These studies demonstrated that the SI could help evaluate the adequacy of fluid resuscitation and the potential response to additional fluid. It can predict the presence of lactic acidosis. The SI also helps predict the development of organ failure and mortality. Consequently, this easily available bedside measurement has utility in the identification, management and prediction of prognosis in patients with sepsis.

Primary coenzyme Q10 deficiency presenting as fatal neonatal multiorgan failure.

Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 µM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis.

Intermittent Cold-Blood Cardioplegia and Its Impact on Myocardial Acidosis during Coronary Bypass Surgery.

BACKGROUND: The purpose of the study was to assess the degree of myocardial acidosis in patients undergoing elective coronary bypass surgery, in whom intermittent cold-blood cardioplegia (ICBC) was used for myocardial protection. The results of this study are presented in comparison to those of a previous trial conducted by the same investigators, using a similar methodology, but with intermittent warm-blood cardioplegia (IWBC). PATIENTS AND METHODS: In 15 patients undergoing elective myocardial revascularization with ICBC for myocardial protection, metabolic changes of global ischemia indicators, lactate and pH values (measured simultaneously in coronary sinus and arterial blood) were analyzed. Lactate concentrations and pH values were measured at the beginning and the end of each cardioplegia administration, and the change-overtime analysis of the values was performed. For comparison with the results of the previous study (IWBC method) consisting of 12 patients, the analysis of variance with repeated measurements, including tests for a crossover, group, and time effect were used. RESULTS: Using the ICBC method, as compared with IWBC, no significant difference in the lactate production was observed during the first two successive cardioplegia administrations. During the third and fourth administrations, especially at the end of reperfusions, ICBC patients had a significantly lower lactate release and higher pH values, as compared with IWBC patients. CONCLUSION: Our results suggest that ICBC has an inhibiting effect on potentially progressive myocardial acidosis during cross-clamp period.

Microcirculatory perfusion shift in the gut wall layers induced by extracorporeal circulation.

OBJECTIVE: Extracorporeal circulation (ECC) is regularly applied to maintain organ perfusion during major aortic and cardiovascular surgery. During thoracoabdominal aortic repair, ECC-driven selective visceral arterial perfusion (SVP) results in changed microcirculatory perfusion (shift from the muscularis toward the mucosal small intestinal layer) in conjunction with macrohemodynamic hypoperfusion. The underlying mechanism, however, is unclear. Therefore, the aim of this study was to assess in a porcine model whether ECC itself or the hypoperfusion induced by SVP is responsible for the mucosal/muscular shift in the small intestinal wall. METHODS: A thoracoabdominal aortic approach was performed in 15 healthy pigs divided equally into three groups: group I, control; group II, thoracic aortic cross-clamping with distal aortic perfusion; and group III, thoracic aortic cross-clamping with distal aortic perfusion and SVP. Macrocirculatory and microcirculatory blood flow was assessed by transit time ultrasound volume flow measurement and fluorescent microspheres. In addition, markers for metabolism and intestinal ischemia-reperfusion injury were determined. RESULTS: ECC with a roller pump induced a significant switch from the muscularis and mucosal layer of the small intestine, even with adequate macrocirculation (mucosal/muscular perfusion ratio: group I vs II, P = .005; group I vs III, P = .0018). Furthermore, the oxygen extraction ratio increased significantly in groups II (>30%) and III (>40%) in the beginning of the ECC compared with the control (group I vs II, P = .0037; group I vs III, P = .0062). Lactate concentrations and pH values did not differ between groups I and II; but group III demonstrated a significant shifting toward a lactate-associated acidosis (lactate: group I vs III, P = .0031; pH: group I vs III, P = .0001). CONCLUSIONS: We demonstrated a significant shifting between the small intestinal gut wall layers induced by roller pump-driven ECC. The shift occurs independently of macrohemodynamics, with a significant effect on aerobic metabolism in the gut wall. Consequently, an optimal intestinal perfusion cannot be guaranteed by a roller pump; therefore, perfusion techniques need to be optimized.

D-lactic acidosis mediated neuronal encephalopathy in acute lymphoblastic leukemia patient: an under diagnosis.

BACKGROUND: D-lactic acidosis, also referred as D-lactate encephalopathy, has been reported in patients with short bowl syndrome (SBS). CASE REPORT: The neurologic symptoms include altered mental status, slurred speech, and ataxia. Onset of neurological symptoms is accompanied by metabolic acidosis and high anion gap. We present here a case of D-lactic acidosis in a patient with acute lymphoblastic leukemia (ALL) who developed severe neurological symptoms and metabolic acidosis due to vancomycin-resistant enterococci (VRE) infection, and elevated D-lactic acid.