Diabetic ketoacidosis (DKA) is the result of a critical relative

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1 DOI: /SUR/2015/33 Case Report Diabetic Ketoacidosis Precipitated by Leptospira and Hepatitis: A Management Protocol Lalit Kumar Dhoka 1, Swapnali Lalit Dhoka 1, Swapnil Sunil Bumb 2 1 Consultant, Pritam Children Hospital, Pune, Maharashtra, India, 2 Assistant Professor, Department of Public Health Dentistry, ACPM Dhule Dental College, Dhule, Maharashtra, India Abstract Acute kidney injury (AKI) is a rare but potentially fatal complication of diabetic ketoacidosis (DKA). The associated liver failure and sepsis further challenged the management of DKA. We present a case of an 11-year-old boy presenting with severe DKA being precipitated by hepatitis A virus and leptospira co-infection. The patient presented with severe metabolic acidosis and features of cerebral edema and developed oliguric AKI. In addition, rhabdomyolysis was noted during the course of DKA which probably contributed to the AKI. We, therefore, describe the difficulties faced and the steps taken differently from usual DKA management to manage this case. Keywords: Acute kidney injury, Diabetic ketoacidosis, Rhabdomyolysis INTRODUCTION Diabetic ketoacidosis (DKA) is the result of a critical relative or absolute deficit of insulin, resulting in intracellular starvation of insulin-dependent tissues (muscle, liver, and adipose), stimulating the release of the counter-regulatory hormones glucagon, catecholamines, cortisol, and growth hormone. 1 They stimulate lipolysis and proteolysis, hepatic and renal glucose production, and hepatic oxidation of fatty acid to ketone bodies. 2 This results in hyperglycemia, glycosuria, osmotic diuresis leading to progressive dehydration, diminished tissue perfusion and increasing acidosis which is responsible for various symptoms and complications associated with DKA. Biochemically it is defined as a venous ph <7.3 or serum bicarbonate concentration <15 mmol/l, serum glucose concentration >200 mg/dl (11 mmol/l) together with ketonemia, glucosuria, and ketonuria. 3 The severity of DKA is determined by the degree of acidosis: 3 Mild: Venous ph >7.2 and <7.3, bicarbonate <15 mmol/l Access this article online Month of Submission : Month of Peer Review : Month of Acceptance : Month of Publishing : Moderate: Venous ph >7.1 and <7.2, bicarbonate <10 mmol/l Severe: Venous ph <7.1, bicarbonate <5 mmol/l. This situation occurs most commonly in new onset type 1diabetes and in patients with known diabetes during infections or other illnesses, or with insulin omission. 4 Most of the mortality in DKA occurs in children with cerebral edema, accounting for 57-87% of deaths. 5 Other causes of morbidity and mortality include sepsis and secondary infection, electrolyte abnormalities (hypokalemia, hypophosphatemia), arrhythmias, rhabdomyolysis, thrombosis, pneumomediastinum, subcutaneous emphysema, and pulmonary edema. 3 Rhabdomyolysis may result in renal failure, compartment syndrome, severe hyperkalemia and other electrolyte disturbance leading to arrhythmias. Acute kidney injury (AKI) is mostly pre-renal due to volume depletion and is rare in children. Management of DKA involves correction of dehydration, insulin therapy, and management of associated complications. With severe DKA or if there are other factors increasing the risk for cerebral edema (age under 5 years, low partial pressure of carbon dioxide, high serum urea nitrogen, greater acidosis at the time of presentation), an intensive care facility is appropriate. 3 Typical patients require an initial fluid Corresponding Author: Dr. Lalit Kumar Dhoka, Pritam Hospital, Pune Nasik Road, Bhosari, Pune , Maharashtra, India. pritamhospital@gmail.com 18

2 bolus of 10 ml/kg of intravenous (IV) fluids (0.9% saline or other isotonic fluids) that may be repeated if ongoing hemodynamic instability is present. The average degree of dehydration for most patients is approximately 7-9% of body weight, and this figure is used as the basis for determining the total volume of fluids to be replaced. The estimated fluid deficit should be replaced over h along with maintenance fluid requirements, generally initially with 0.9% saline, then transitioning to 0.45% saline after several hours to avoid rapid fall in serum osmolarity. Potassium of 40 meq/l should be added after the patient starts passing urine. 6 Insulin should be started after initial fluid expansion. 0.1 U/kg/h is given as a continuous infusion until ketoacidosis resolves (ph>7.3, HCO 3 >15, normalization of anion gap). A bolus dose of insulin is not indicated and may increase the risk of cerebral edema. 7 In case of persistent acidosis (bicarbonate value <10 mmol/l after 8-10 h of treatment), insulin dilution and rate of administration should be checked, and fresh preparation made. 8 IV fluids can be stopped 1-2 h after substantial consumption of oral fluids without vomiting. Subcutaneous insulin injection can be started when IV fluids are no longer needed. Care should be taken to prevent cerebral edema, and IV mannitol should be given in the case of any signs suggestive of same. We report a case of DKA being precipitated by hepatitis A and leptospira co-infection in a child with Type 1 diabetes mellitus resulting in rhabdomyolysis, hepatic, and renal failure. The hepatic and renal failure made management of the cerebral edema in DKA even more difficult. This was a unique presentation of DKA, which has never been described previously as far as we know. CASE REPORT The 11-year-male child, diagnosed to have Type 1 diabetes mellitus 4 years previously was known to have poor compliance to his insulin regimen with a history of recurrent episodes of hypoglycemic seizures. He presented with fever of 4 days duration, recurrent vomiting of 1-day duration and altered consciousness with onset within a few hours prior to presentation to the hospital. On initial evaluation child was lethargic, irritable, Glasgow coma scale was 13, with severe dehydration and compensated shock. Heart rate was-160/min, absent peripheral pulse, and weak central pulse, delayed capillary refill time (5 s), and cold peripheries. The systolic blood pressure was 110 mmhg; he had tachypnea and Kussmaul s breathing. His saturation was 100% at room air. Initial venous gas showed a ph of 6.97, bicarbonate of 4.9 mmol/l, and base deficit of Blood glucose checked by bedside glucometer showed level more than 500 mg/dl and urine by bedside dipstick showed large amount (4+) of ketones. He was managed as per International Society for Pediatric and Adolescent Diabetes Guidelines. A normal saline bolus of 10 ml/kg was given over 1 h after which shock improved and then he was continued on dehydration correction targeted over 48 h. Initial fluid being normal saline with 40 meq/l of potassium. Insulin infusion was started at 0.1 unit/kg/h, after 1 h of fluid resuscitation. At 4 h of admission, he developed generalized seizure which was aborted with IV midazolam and loading of mannitol (1 g/kg) and 3% saline (5 ml/kg) was given. He was electively intubated and ventilated. By 8 h of admission, he developed hypotensive shock requiring fluid bolus and inotropic support (dopamine and adrenaline) to stabilize hemodynamics. By 25 h of admission, there was again an episode hemodynamic instability requiring cardiopulmonary resuscitation. Bicarbonate was also given to restore stable hemodynamics, keeping a possibility of acidosis induced myocardial instability. Further insulin infusion up to 0.2 units/kg/h was required to get an adequate control of blood sugar, acidosis, and hyperkalemia. Initially had good urine output, but developed oliguria by 20 h and also had high admission creatinine. Urine output decreased progressively with rising creatinine and developed anuria by 36 h along with refractory metabolic acidosis, hyperkalemia, and hyperglycemia hence Sustained low-efficiency daily dialysis (SLEDD) was started. After dialysis, there was steady improvement in biochemical parameters (acidosis and hyperkalemia) but as anuria persisted he was started on restricted fluid replacement for AKI. The sequential laboratory reports are in Table 1. Initial investigation showed normal phosphate and slightly increased creatine phosphokinase (CPK) levels, but it was found to be increased further on repeat evaluation at day 4 of admission along with low phosphorus and elevated lactate dehydrogenase levels, suggesting rhabdomyolysis (Table 1 and 2). As he had rapidly rising liver transaminases (serum glutamic-oxaloacetic transaminase: 6318-D1 and D3) the causes of hepatitis were looked into revealing positive serology for hepatitis A and leptospirosis. Supportive care for hepatitis A and specific antibiotic cover for leptospira was given. The patient improved with above management and was extubated on day 5 of admission along with cessation of inotropic support and insulin infusion. However, child remained persistently oliguric and had high creatinine 19

3 Table 1: Laboratory investigations Date Nov 1 st Nov 2 nd Nov 3 rd Nov 4 th Nov 5 th Time (h) Hemoglobin (g/dl) Total count (thousand) Platelet (lakh) BUN (mg/dl) Creatinine (mg/dl) Sodium (meq/l) Potassium (meq/l) Phosphorus (mg/dl) CPK (IU/L) LDH (U/L) 9870 Bilirubin total (mg/dl) Bilirubin direct (mg/dl) AST (IU/L) ALT (IU/L) Total protein (g/dl) Albumin (g/dl) ALP (IU/L) 533 Ammonia (mmol/l) PT INR PTT CRP (mg/dl) HbA1C (mmol/mol) 11.1 Anti HAV IgM Positive Leptospira IgM Positive BUN: Blood urea nitrogen, CPK: Creatine phosphokinase, LDH: Lactate dehydrogenase, AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, ALP: Alkaline phosphatase, PT: Prothrombin time, INR: International normalized ratio, PTT: Partial thromboplastin time, CRP: C reactive protein, HbA1C: Glycated hemoglobin, IgM: Immunoglobulin M, HAV: Hepatitis A virus requiring alternate day hemodialysis for volume control and adequate clearance. In view of the child remaining oliguric and dialysis dependent even 4 weeks after therapy, a kidney biopsy was done keeping the possibility of acute cortical necrosis and pigmentary nephropathy. Biopsy report suggested severe acute tubular necrosis and tubules clogged with myoglobin pigment which was considered secondary to rhabdomyolysis. At the end of 8 weeks of dialysis, his renal functions and urine output improved. DISCUSSION In DKA, pre-renal AKI is commonly encountered as a result of volume depletion but resolves with treatment as hydration improves. Intrinsic AKI is a rare complication of DKA in children. 9 Leptospirosis can present as Weil s disease which, primarily manifests as profound jaundice, renal dysfunction, hepatic necrosis, pulmonary dysfunction, and hemorrhagic diathesis. 10 Weil s disease in our patient possibly led to AKI. Other contributing factors could be hypovolemia, sepsis or rhabdomyolysis. 9 However, the kidney biopsy concluded that it was secondary to rhabdomyolysis as myoglobin pigment had clogged the entire tubules with some evidence of interstitial nephritis. Subclinical rhabdomyolysis is known to occur in DKA due to electrolyte abnormalities such as hypophosphatemia, hypokalemia, and hyponatremia, but renal failure is not common. 11 In our patient, low phosphate levels and ketosis as a result of DKA along with Weil s disease possibly contributed to the development of rhabdomyolysis. The cellular injury in hypophosphatemia is due to severe depletion of ATP content. 12 The most sensitive laboratory marker for rhabdomyolysis is serum CPK level which increases in the first 12 h, peaks in h and declines at the rate of 36-40%/day. 11 A similar trend was seen in our patient (Table 1). The occurrence of acute renal kidney injury due to rhabdomyolysis in DKA is potentially lethal and increases the mortality to 50%. 11 Concomitant presence of oliguric AKI with DKA posed a challenge in terms of fluid management as former requires fluid restriction which is contrary to the requirement of fluid therapy for reversal of diabetic ketosis. The renal failure resulted in refractory hyperkalemia and persistent metabolic acidosis. As this could not be managed with routine DKA management protocol, renal replacement therapy in the form of SLEDD was initiated (as child was hemodynamically unstable) and continued. Metabolic parameters showed remarkable improvement as depicted in Table 1. 20

4 Table 2: Laboratory investigation Date Nov 7 th Nov 9 th Nov 12 th Nov 18 th Time Hemoglobin (g/dl) Total count (thousand) Platelet count (lakh) BUN (mg/dl) Creatinine (mg/dl) Sodium (meq/l) 145 Potassium (meq/l) 3.6 Phosphorus (mg/dl) CPK (IU/L) LDH (U/L) Bilirubin total (mg/dl) Bilirubin direct (mg/dl) AST (IU/L) ALT (IU/L) Total protein (g/dl) Albumin (g/dl) ALP (IU/L) Ammonia (mmol/l) PT 32 INR 2.6 PTT 44 CRP (mg/dl) 10.7 BUN: Blood urea nitrogen, CPK: Creatine phosphokinase, LDH: Lactate dehydrogenase, AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, ALP: Alkaline Phosphatase, PT: Prothrombin time, INR: International normalized ratio, PTT: Partial thromboplastin time, CRP: C reactive protein, HbA1C: Glycated hemoglobin IgM: Immunoglobulin M, HAV: Hepatitis A virus Our patient had co-infection with hepatitis A. This coinfection has been reported before. 13 Both are waterborne from contaminated water. The spirochete penetrates skin of persons wading through sewage contaminated water where hepatitis A is acquired though drinking contaminated water and while both infections can spread in the same milieu but as their incubation periods are different, and its manifestations appeared simultaneously it suggests they were acquired at different points of time. Another problem faced in our case was persistent acidosis. Persistent acidosis in DKA, defined as bicarbonate value <10 mmol/l after 8-10 h of treatment, is usually caused by inadequate insulin effect. Rare causes include lactic acidosis or inadequate renal handling of hydrogen ion as a result of renal hypo perfusion. 8 For persistent acidosis, hyperglycemia and hyperkalemia, a possibility of an inadequate drug effect was kept, and adequate insulin delivery was ensured but there was no significant change. It was then when the rate of insulin infusion was increased. Hence in our patient, it was relative insulin resistance state. Insulin requirements are altered in renal failure, either increased due to insulin resistance or decreased due to impaired clearance of circulating insulin. 14 Associated morbidity was a coexistent acute liver failure due to hepatitis A and leptospira co-infection. Literature has reported DKA complicated by hypovolemic shock, infection and profound metabolic decompensation leading to hypoxic hepatopathy in infants. 15 However, there has been no reported DKA case with a severe liver injury with coexisting hepatitis A virus and leptospirosis. This affected the clinical course in our patient leading to delayed recovery. CONCLUSION The conclusion which can be drawn is that early initiation of renal replacement therapy may improve the potentially poor outcome of patients with AKI associated with DKA. REFERENCES 1. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009;32: Foster DW, McGarry JD. The metabolic derangements and treatment of diabetic ketoacidosis. N Engl J Med 1983;309: Wolfsdorf J, Craig ME, Daneman D, Dunger D, Edge J, Lee W, et al. Diabetic ketoacidosis in children and adolescents with diabetes. Pediatr Diabetes 2009;10: Maniatis AK, Goehrig SH, Gao D, Rewers A, Walravens P, Klingensmith GJ. Increased incidence and severity of diabetic ketoacidosis among uninsured children with newly diagnosed type 1 diabetes mellitus. Pediatr Diabetes 2005;6: Muir AB, Quisling RG, Yang MC, Rosenbloom AL. Cerebral edema in childhood diabetic ketoacidosis: Natural history, radiographic findings, and early identification. Diabetes Care 2004;27: Wolfsdorf J, Glaser N, Sperling MA. American Diabetes Association. Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care 2006;29: Edge J, Jakes R, Roy Y, Hawkins M, Winter D, Ford-Adams ME, et al. The UK case-control study of cerebral oedema complicating diabetic ketoacidosis in children. Diabetologia 2006;49: Rosenbloom AL, Hanas R. Diabetic ketoacidosis (DKA): Treatment guidelines. Clin Pediatr (Phila) 1996;35: Orban JC, Maizière EM, Ghaddab A, Van Obberghen E, Ichai C. Incidence and characteristics of acute kidney injury in severe diabetic ketoacidosis. PLoS One 2014;9:e Maroun E, Kushawaha A, El-Charabaty E, Mobarakai N, El-Sayegh S. Fulminant Leptospirosis (Weil s disease) in an urban setting as an overlooked cause of multiorgan failure: A case report. J Med Case Rep 2011;5: Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians. Crit Care 2005;9: Knochel JP, Barcenas C, Cotton JR, Fuller TJ, Haller R, 21

5 Carter NW. Hypophosphatemia and rhabdomyolysis. J Clin Invest 1978;62: Alves AP, Moura DC, Spolti GP. Co-infection with hepatitis A and leptospirosis in the Amazon region: Report of two cases. Trop Gastroenterol 2011;32: Poovazhagi V, Senguttuvan P, Padmaraj R. Outcome of acute renal failure in children with diabetic keto acidosis (DKA). Pediatr Oncall 2011;8. Available from: pediatriconcall.com/journal/article/fulltext.aspx?artid= 417&type=J&tid=&imgid=&reportid=97&tbltype=. [Last accessed on 2011 Aug 01]. 15. Szypowska A, Skórka A, Pankowska E. Acute hypoxic hepatopathy: Diabetic ketoacidosis complication in an infant newly diagnosed with type 1 diabetes mellitus. Pediatr Endocrinol Diabetes Metab 2008;14: How to cite this article: Dhoka LK, Dhoka SL, Bumb SS. Diabetic Ketoacidosis Precipitated by Leptospira and Hepatitis: A Management Protocol. IJSS Journal of Surgery. 2015;1(5): Source of Support: Nil, Conflict of Interest: None declared. 22