Lyle E. Fisher

Cytokine response to diabetic ketoacidosis and its treatment

The objectives of this study were to monitor plasma cytokines as markers of cellular activation and as potential markers for the progression of the acute complications of diabetic ketoacidosis (DKA). Blood samples were obtained prior to, during and after treatment of severe DKA (pH < 7.2) in six children and adolescents. Plasma IL-10, IL-1beta, TNF-alpha, IL-6, IL-8 and IL-2 cytokine levels were assayed by ELISA at each of the time points. Prior to treatment, elevations of multiple cytokines were found, the highest being IL-10. Treatment of DKA resulted in a significant decrease of IL-10 at 6-8 h (p = 0.0062), and further increases in the inflammatory cytokines at 6-8 h and/or 24 h vs 120 h (baseline): IL-1beta (p =.0048); TNF-alpha (p =.0188) and IL-8 (p =.0048). This study strengthens the hypothesis that the metabolic crisis of DKA, and its treatment, have differential effects on cellular activation and cytokine release. The time frame for the increase in inflammatory cytokines correlates with the reported progression of subclinical brain edema, interstitial pulmonary edema and the development of clinical brain edema.

Acute rhabdomyolysis complicating status asthmaticus in children: case series and review.

Objectives: To describe a case series of 4 children who developed acute rhabdomyolysis as a complication of acute respiratory failure secondary to status asthmaticus. Methods: A retrospective review of all children who were admitted to our pediatric intensive care unit (PICU) with status asthmaticus from November 1998 through July 2004 was performed and all children who developed acute rhabdomyolysis, defined as a 5-fold increase above the upper limit of normal in the serum creatine phosphokinase (CPK) concentration (CPK ≥1250 IU/L), were identified. Demographic and clinical data were abstracted from the medical record. Results: During the study period, 108 children with status asthmaticus were admitted to our PICU (3.6% of all admissions). Four children (age 12-19 years) developed acute respiratory failure requiring mechanical ventilation, and all 4 of these children (3.7% of all children with status asthmaticus admitted to the PICU) developed acute rhabdomyolysis. The 4 children who developed acute rhabdomyolysis were older than the children with status asthmaticus, without rhabdomyolysis (median age 15 years vs. 5 years). Conclusions: Acute rhabdomyolysis complicating status asthmaticus may be more common than previously ascertained. We therefore suggest that CPK levels should be followed closely in all children with status asthmaticus and acute respiratory failure. The early presentation of rhabdomyolysis in the current series suggests that factors other than corticosteroids and neuromuscular blockers are potentially involved. Mechanical ventilation and older age seem to be significant risk factors for rhabdomyolysis, perhaps implicating a mechanism similar to the pathogenesis of severe exercise-related rhabdomyolysis. Further clinical study of the incidence and causative factors of rhabdomyolysis in this population is warranted.

A tale of two sisters.

A 4-year-old previously healthy African-Americangirlwas brought to a rural hospital emergency department (ED) with the acute onset of fever, vomiting, somnolence, and seizures. She seemed in her usual state of good health until she was found outside, by her father, near the family’s barn where she had been playing. She was lying unconscious with generalized tonicclonic movements. According to emergency medical services personnel, she had vomited ‘‘a few times’’ and had been incontinent of urine at the scene, although she was no longer seizing. Upon arrival in the ED, the child was obtunded and ill-appearing and exhibited labored respirations. Her vital signs included a rectal temperature of 39.58C; heart rate, 78 beats per minute; respiratory rate, 38 breaths per minute; blood pressure, 110/65 mmHg; and hemoglobin oxygen saturation, 93%. Her pupils were 1 to 2 mm in diameter and sluggishly reactive. The mucus membranes were moist with copious, white, frothy oral secretions. Her lung examination revealed bilateral wheezing with diminished breath sounds bilaterally. Cardiovascular examination was significant only for a low heart rate. Peripheral pulses were strong and equal bilaterally without brachiofemoral delay. She had no abdominal tenderness, distension, or hepatosplenomegaly.Her skin was warm and clammy to touch with capillary refill of less than 2 seconds. There was no rash. She did not open her eyes to voice or pain, but withdrew to pain. Her deep tendon reflexes were normal. Her initial laboratory parameters upon presentation to the ED were as follows: sodium, 141 mmol/L; potassium, 3.7 mmol/L; chloride, 112 mmol/L; bicarbonate, 20 mmol/L; calcium, 8.4 mg/dL; magnesium, 2.1 mg/ dL, phosphorus, 5.9 mg/dL; blood urea nitrogen, 16 mg/dL; creatinine, 0.6 mg/ dL; glucose, 233mg/dL; albumin, 3.6 g/ dL; total protein, 5.9 g/dL; alanine aminotransferase, 11 U/L; aspartate aminotransferase, 39 U/L; total bilirubin, 0.6 mg/dL; and alkaline phosphatase, 202 U/L. An arterial blood gas analysis was pH 7.20; PaCO2, 58 mm Hg; PaO2, 88 mm Hg; and base excess, 6.5 mmol/L. A complete blood count revealed hemoglobin of 10.1 g/dL; hematocrit, 30.4%; platelets, 213,000 cells/mL; and white blood cells, 1500 cells/mL. A chest radiograph showed a normal cardiothymic silhouette and bilateral opacities consistent with either aspiration pneumonitis or noncardiogenic pulmonary edema. Intravenous accesswas secured, and she is tracheally intubated for airway protection and mechanical ventilatory support. Computed tomography of the head and lumbar puncture were obtained, the results of which were both essentially normal. Ceftriaxone, 50 mg/kg, and phenytoin, 20 mg/kg, were administered parenterally. Shortly thereafter, the child’s 3year-old sister presented with a similar constellation of symptoms, including lethargy, vomiting, and diarrhea. Her temperature was 36.88C; heart rate, 83 beats per minute; respiratory rate, 28 breaths per minute; and blood pressure, 83/42 mm Hg. Her pupils were 1 mm in diameter, and her respirations were shallow. Intravenous access was secured, and 20 mL/kg normal saline was administered. She was tracheally intubated for airway protection and mechanical ventilatory support. Naloxone, 0.1 mg/kg, was administered parenterally to both children without any significant improvement in sensorium. Can you pick your poison? A Tale of Two Sisters Pick Your Poison

PENTOXIFYLLINE RESCUE PRESERVES LUNG FUNCTION IN ISOLATED CANINE LUNGS INJURED WITH PHORBOL MYRISTATE ACETATE

OBJECTIVE We hypothesized that pentoxifylline, administered after phorbol myristate acetate (PMA), would diminish the severity of lung injury. SETTING Animal research laboratory. DESIGN Comparative study. SUBJECTS Mongrel dogs (n = 33). INTERVENTIONS Baseline measurements were obtained from the isolated blood-perfused dog lung lobes after 1 h of stable perfusion and ventilation. Four different measures of lung compliance were obtained along with WBC and neutrophil counts. Pulmonary vascular resistance (PVR) and capillary filtration coefficient (Kf) were calculated, and the ratio of a normalized maximal enzymatic conversion rate to the Michaelis-Menten constant (Amax/Km) was used to assess perfused capillary surface area. The control lobes (n = 8) were ventilated and perfused for an additional 40 min while the injured lobes (n = 17) received PMA (0.1 microg/mL of perfusate). The pentoxifylline-protected lobes (n = 8) were treated with pentoxifylline (1 mg/mL of perfusate) 10 min after injury with PMA. All measurements were then repeated. MEASUREMENT AND MAIN RESULTS The three groups did not differ significantly at baseline. The control lobes remained relatively stable over time. The injured lobes demonstrated marked deterioration in compliance: 8.79 +/- 0.7 to 5.97 +/- 0.59 mL/cm H(2)O (p < 0.05) vs 10.1 +/- 1.0 to 8.07 +/- 0.72 mL/cm H(2)O and 9.6 +/- 1.1 to 9.9 +/- 0.85 mL/cm H(2)O in the control and protected lobes, respectively. Both groups receiving PMA had similar drops in WBC and neutrophil counts, but the pentoxifylline-protected lobes had preservation of all four compliance measures. PVR increased from 37.8 +/- 1.8 to 118.6 +/- 12.7 cm H(2)O/L/min (p < 0.05) in the injured lobes vs 35.4 +/- 0.5 to 36.3 +/- 2.8 cm H(2)O/L/min and 40.4 +/- 0.04 to 46.7 +/- 2.8 cm H(2)O/L/min (p < 0.05) in the control and protected lobes, respectively. Kf increased < 25% in the protected group but more than tripled in the injured group. Amax/Km dropped from 559 +/- 36 to 441 +/- 33 mL/min (p < 0.05) in the injured lobes vs 507 +/- 14 to 490 +/- 17 mL/min and 609 +/- 34 to 616 +/- 37 mL/min in the control and pentoxifylline-protected lobes, respectively. CONCLUSIONS The use of pentoxifylline as a rescue agent prevented the PMA-induced deterioration of lung compliance, vascular integrity, and endothelial metabolic function in this acute lung injury model, despite significant pulmonary neutrophil sequestration.