Phase II study of a moderate-intensity preparative regimen with allogeneic peripheral blood stem cell transplantation for hematologic diseases: the Texas Transplant Consortium experience.

Conventional preparative regimens for allogeneic stem cell transplantation are associated with excessive regimen-related toxicity (RRT) in some patients because of underlying comorbidities, advanced age, or prior treatment. We studied a preparative regimen designed to reduce RRT, yet allow for adequate engraftment and development of a graft-versus-malignancy effect. Thirty patients (median age, 57 years) were entered on study. Twenty-nine patientsreceived stem cells from HLA-identical siblings and 1 from a sibling mismatched for 1 antigen at the A locus. Sixteen patients had received previous stem cell transplants (6 allogeneic and 10 autologous). The preparative regimen consisted of fludarabine 30 mg/M2 per day IV on day -10 to day -5, busulfan 1 mg/kg per dose PO (n = 6) or 0.8 mg/kg per dose IV (n = 24) for 8 doses every 6 hours on day -6 to day -5, and horse-derived antithymocyte globulin 5 mg/kg per day IV (n = 12) or 15 mg/kg per day IV (n = 18) on day -4 to day -1. GVHD prophylaxis consisted of cyclosporine (CYA) 3 mg/kg BID PO starting on day -3 (n = 13) or CYA and methotrexate 15 mg/m2 IV on day +1 and 10 mg/m2 IV on day +3 and day +6 (n = 17). The median number of CD34 cells transplanted was 3.19 x 10(6)/kg. All patients demonstrated recovery of hematopoietic function. Twenty-six (89%) of 29 evaluable patients achieved greater than 90% donor cell chimerism before day 100. Three patients never achieved greater than 90% donor chimerism, and another 3 patients subsequently lost donor chimerism. All 6 of these patients had autologous reconstitution with progressive disease. RRT was minimal; 7 patients had greater than grade II nonhematologic toxicity and there were no toxic deaths attributable to the conditioning regimen. Transplantation-related mortality was 7% (95% confidence interval [CI], 6%-8%) at 3 months and 28% (95% CI, 23%-34%) at 12 months after transplantation. Non-relapse-related mortality was most often due to infection. Grade II or greater GVHD developed in 56% of evaluable patients, and all patients with disease response developed GVHD. Actuarial estimates of overall and disease-free survival at 12 months were 52% (95% CI, 43%-63%) and 30% (95% CI, 24%-37%), respectively. Although this preparative regimen allowed adequate engraftment with minimal RRT, GVHD and infectious complications caused significant morbidity and mortality. Further study to define appropriate patient populations for this regimen, while limiting GVHD and infection risks, is needed.

Nonmyeloablative allogeneic peripheral blood stem cell transplantation for multifocal extramedullary plasmacytomas progressing after autologous transplantation.

Multifocal extramedullary plasmacytomas (EMP) are an uncommon manifestation of plasma cell malignancies. We report two patients with multiple EMP who developed rapidly progressive and ultimately fatal disease shortly after undergoing nonmyeloablative, matched-related donor allogeneic peripheral blood stem cell transplantation (PBSCT). We have not observed a similar course in patients transplanted for multiple myeloma without extramedullary manifestations and hypothesize that the intense immunosuppression associated with the fludarabine, busulfan and anti-thymocyte globulin conditioning regimen may have contributed to rapid disease progression in the two EMP patients. Our observations support the assertion that extramedullary disease is a marker for an aggressive, refractory plasma cell malignancy and suggest that patients should be treated intensively from the time of diagnosis. The utility of a graft-versus-tumor effect and the role of nonmyeloablative allogeneic PBSCT is yet to be defined in patients with extramedullary plasma cell malignancies, but it is logical to consider using it at the time of minimal residual disease rather than at disease relapse or progression. Nevertheless, we recommend circumspection in the administration of highly immunosuppressive conditioning regimens to patients with refractory EMP and encourage further clinical research in this area.

Direct effects of propofol on myocardial and vascular tissue from mature and immature rats.

OBJECTIVE: To determine the effect of age on the direct myocardial and vascular effects of propofol in rats. DESIGN: Randomized, prospective with repeated measures. SETTING: University research laboratory. PARTICIPANTS: Myocardial and aortic tissue from 12 immature (4-week-old) and 12 mature (16-week-old) male Sprague-Dawley rats. INTERVENTIONS: Change in force of contraction was measured in isolated myocardial strips or in isolated descending thoracic aorta rings during exposure to propofol or intralipid. MEASUREMENTS AND MAIN RESULTS: Propofol produced a dose-dependent decrease in vascular tone (p < 0.05). This effect was similar for intralipid. Propofol was more potent in the younger animals (EC(50), 5.3 microg/mL [confidence interval, 2.5 to 11.1] for 4-week-old and 26.6 microg/mL [confidence interval, 6.8 to 103.7] for 16-week-old rats; p < 0.05). In contrast, propofol produced a dose-dependent decrease in contractility (p = 0.001), whereas intralipid produced no decrease in contractility. CONCLUSIONS: Although propofol does produce a dose-dependent decrease in contractility, this effect is similar at different ages. Propofol produces more direct vascular relaxation in the immature tissue. Propofol's direct cardiovascular effect and its indirect cardiovascular effects should be considered in the young and old, especially when cardiovascular reserve is limited.

Laryngospasm and diaphragmatic arrest in immature dogs after laryngeal acid exposure: a possible model for sudden infant death syndrome.

Laryngopharyngeal reflux has been proposed as a possible cause of sudden infant death syndrome (SIDS). We investigated the efferent laryngeal and diaphragmatic responses to acid exposure on the laryngeal mucosa using a neonatal canine model. Electromyographic (EMG) recordings from the thyroarytenoid muscle and the diaphragm were measured with hooked-wire electrodes. Reproducible laryngospasm responses occurred in all animals after laryngeal exposure to hydrochloric acid at pH 2.0 or less. Laryngospasm occurred in combination with tachypnea and increased diaphragmatic activity in most of the animals. Laryngospasm was associated with prolonged apnea and total cessation of diaphragmatic EMG activity in 1 animal, and in another, initial tachypnea was followed by erratic diaphragmatic activity and brief apnea. Laryngeal acid exposure (below pH 2.0) causes laryngospasm and may result in paradoxical apneic events in neonatal dogs. Acid-induced, laryngospasm-associated apnea may represent a potential cause of SIDS, and the immature dog appears to be an excellent model for further investigations.

Graft failure in a patient with systemic lupus erythematosus (SLE) treated with high-dose immunosuppression and autologous stem cell rescue.

A 32-year-old female with WHO grade IV, dialysis dependent, lupus nephritis was treated with high-dose immunosuppression and autologous stem cell rescue. Stem cells were mobilized with cyclophosphamide (CY) and G-CSF, and 4.07 x 10(6) CD34+ cells/kg were obtained after CD34+ cell selection using the CellPro column. The preparative regimen consisted of CY, and antithymocyte globulin (ATG), with methylprednisolone. After apparent primary engraftment of neutrophils on day 9, the patient developed recurrent neutropenia on day 19. She showed no evidence of engraftment by day 35, and back-up unmanipulated stem cells were given without effect. Subsequently, she received unmanipulated peripheral stem cells (2 x 10(6) CD34+ cells/kg) from an HLA-identical sibling. The patient remained pancytopenic and expired on day 62 from disseminated fungal infection. An autopsy revealed no evidence of hematopoietic recovery. Progenitor cell assays were performed with the patient's stem cells, which were collected prior to transplantation, and serum collected day 27. Morphologic examination of the patient's cell colonies grown in the presence of her serum revealed abnormal shapes and non-adherent cells. There were significantly fewer BFU-e colonies and a trend toward fewer CFU-GM colonies with the patient's cells and serum compared to normal donor cells. We concluded that a substance present in her serum mediated graft failure and prevented engraftment after additional stem cell infusions.

Treatment of severe thrombocytopenia in alloimmunized, transfusion-refractory patients.

A significant proportion of patients with hematologic malignancies who are exposed to multiple transfusions will develop alloantibodies to platelet human leukocyte antigens (HLA), resulting in poor responses to subsequent platelet transfusions. Transfusion of HLA-identical platelets is an effective method of platelet support in these patients, but perfectly HLA-matched platelets are often not available. In this paper, we review the recent literature on platelet transfusion support in alloimmunized individuals and illustrate alternative management strategies with cases from our own practice.

Allogeneic bone marrow transplantation at Wilford Hall U.S. Air Force Medical Center: 1987-1999.

Wilford Hall Medical Center (WHMC), at Lackland Air Force Base in San Antonio, Texas, is the only center within the U.S. Department of Defense at which allogeneic bone marrow transplantation (BMT) is performed. From the inception of the BMT program in 1987 through February 1999, 286 military health care beneficiaries have undergone human leukocyte antigen-matched related donor allogeneic bone marrow transplantation for hematologic disorders. We conducted a retrospective chart review to analyze the outcomes of all allogeneic BMT procedures performed at WHMC through February 1999. Our analysis revealed that allogeneic BMT outcomes compared favorably with those reported by the International Bone Marrow Transplant Registry. The results of this study support the continued designation of the Fisher Bone Marrow Transplant Center at WHMC as a specialty treatment service within the Department of Defense.

Effect of alkalinization of lidocaine on median nerve block.

Median nerve blocks were performed in 10 volunteers in a randomized, double-blind, crossover study to compare the effects of 1% plain lidocaine with 1% lidocaine in sodium bicarbonate 0.1 mmol litre-1. Sensations of hot, cold, pinprick and light touch, compound motor and sensory nerve action potentials, and skin temperature were assessed at 2-min intervals. pH was 6.4 +/- 0.1 for plain lidocaine and 7.7 +/- 0.2 for alkalinized lidocaine (P < 0.001). Alkalinized lidocaine produced more rapid inhibition of compound motor action potentials than plain lidocaine (median 4 (range 2-6) vs 9 (2-14) min) (P = 0.039). Alkalinized lidocaine also produced more rapid onset of inhibition of compound motor than sensory nerve action potentials (4 (2-6) vs 8 (4-12) min) (P = 0.0039). There was no significant difference in any other sensory modality between alkalinized and plain lidocaine. These data suggest that addition of bicarbonate to lidocaine for median nerve block significantly increased the rate of motor block without changing the onset or extent of sensory block.

Vasodilatory actions of the dietary peptide carnosine.

The objective of this study was to test the hypothesis that the dietary dipeptide carnosine (beta-alanine-L-histidine) causes direct decreases in arterial tone. Isolated descending thoracic aortic rings from male Sprague-Dawley rats were used for all studies. Preconstriction of vessels was accomplished with phenylephrine. Carnosine (0.625-20 mM) produced dose-dependent vascular relaxation (P < 0.05) that was independent of endothelium. The constituent amino acid L-histidine did not produce any significant relaxation over the same dose range, whereas beta-alanine actually produced dose-dependent vasoconstriction (P < 0.05). The soluble guanylate cyclase inhibitor methylene blue (10(-5) M) significantly decreased the relaxation produced by carnosine (P < 0.05). Measurement of cyclic GMP in the presence and absence of methylene blue after carnosine and phenylephrine exposure was also done. Methylene blue 10(-5) M resulted in a decrease in cyclic GMP levels from 65.3 +/- 15.6 fmol/mg protein to 8.6 +/- 0.9 fmol/mg of protein (P = 0.001). We conclude that carnosine produces relaxation of isolated rat aorta independent of endothelium. The effect of carnosine is at least in part mediated via cyclic GMP production and is not reproduced by its constituent amino acids, L-histidine and beta-alanine.

Correlation of CD34+ cell counts with volume of bone marrow collected for allogeneic bone marrow harvests.

The quantity of bone marrow collected for allogeneic bone marrow transplantation is based on collecting 10 to 15 cc of bone marrow/kg of recipient weight. We hypothesized that the percentage of CD34+ cells collected during a bone marrow harvest decreased at the end of the harvest because of increasing amounts of peripheral blood contamination. We performed a prospective, blinded study in which we measured CD34+ percentages and cell counts at 200-cc intervals during bone marrow harvests from 11 consecutive human leukocyte antigen (HLA)-matched sibling bone marrow donors. We observed that the percentage of CD34+ cells in aspirated bone marrow did not vary significantly from the start to the end of the bone marrow harvest, and the total number of CD34+ cells/kg increased in a linear fashion, thus disproving our original hypothesis. In conclusion, the percentage of CD34+ cells in aspirated bone marrow will remain constant throughout a bone marrow harvest.

Hemifacial microsomia: anatomical prediction of difficult intubation.

Hemifacial microsomia (HFM) is associated with a difficult airway. We hypothesized that a difficult intubation would be predicted by radiographic evaluation of the severity of mandibular hypoplasia. A retrospective review of anaesthetic and surgical records of 102 children with HFM from 1986 to 1996 was conducted for radiographic classification of mandibular hypoplasia and degree of difficulty with intubation. Intubation was classified as Grade A-easy, Grade B-difficult, or Grade C-very difficult. The mandibular anatomy was categorized as Type I-'mini-mandible', Type II-abnormal condylar size and shape, or Type III-absent ramus, condyle, and temporomandibular joint. In the 82 patients with HFM, 70% were classified as Grade A, 21% had Grade B and 9% had Grade C airways. No patients with Type I mandible had Grade C airway, while 25% of the patients with Type III mandible had Grade C airway. The correlation of the degree of airway difficulty with mandibular type was significant (P=0.001). In 20 patients with bilateral mandibular hypoplasia, 30% had Grade A, 35% had Grade B, and 35% had Grade C airways. We conclude that radiographic classification of mandibular deformity is a useful adjunct for preoperative prediction of airway difficulty in the management of children with unilateral HFM.

Pediatric endotracheal tube selection: a comparison of age-based and height-based criteria.

Many methods are taught and used clinically to determine what size uncuffed endotracheal tube is required for the pediatric patient. The purpose of this study was to compare the effectiveness of two methods of selection used clinically: (1) the traditional age-based (AB) formula; (age in years +16) divided by 4, and (2) the method based on body length using the Broselow pediatric resuscitation tape. Following institutional review board approval, 174 patients were prospectively studied after informed consent was obtained. Uncuffed endotracheal tube size selection was determined by randomly assigning the patient to one of the two groups. The appropriateness of the tube selection was assessed using an audible air leak around the endotracheal tube. No difference was found between the AB group and the resuscitation tape group with respect to selecting the appropriate size of endotracheal tube. Retrospective analysis of all patients found another AB formula that is occasionally used ([age in years +18] divided by 4) to be correct in only 20 (11%) of 174 cases. This was significantly different from the other methods (P < .001). Since the AB formula ([age in years +16] divided by 4) is reliable and easily applied, it appears acceptable for routine anesthesia cases in the pediatric population requiring endotracheal intubation. The AB formula ([age in years +18] divided by 4) should be used cautiously because of the high failure rate. In circumstances in which general information, such as age, is not available and endotracheal intubation is needed, the Broselow tape allows reliable endotracheal tube size identification and should be readily available.

Effects of cardiopulmonary bypass and deep hypothermic circulatory arrest on the thyroid axis during and after repair of congenital heart defects: preservation by deep hypothermia?

UNLABELLED: Thyroid function is altered by cardiopulmonary bypass (CPB) in children. To better understand the cause of altered thyroid hormone levels, we compared the effects on the pituitary-thyroid axis of CPB in 23 children undergoing elective repair of congenital heart defects. Twelve patients underwent CPB with moderate hypothermia without a period of deep hypothermic circulatory arrest (DHCA), and eleven underwent CPB with DHCA. Nine blood samples were collected from each patient before, during, and after CPB. Free T3 (FT3), free T4 (FT4), total T3 (TT3), total T4 (TT4), thyrotropin (TSH), and albumin were measured; concentrations of each decreased significantly with the onset of CPB (P < 0.05). There was a greater decline in hormone than in albumin concentrations, which suggests that factors in addition to hemodilution were present (P < 0.05). TSH concentrations in the DHCA group began to increase during cooling, exceeding baseline values after rewarming and after separation from CPB. Patients undergoing CPB without DHCA had persistently low TSH concentrations (P < 0.05). By Postoperative Days 1 and 2, TSH concentrations in both groups were similar and significantly lower than baseline values (P < 0.001). FT3, FT4, TT3, TT4, and albumin all increased during CPB after an initial decrease. Of these, only albumin and FT4 recovered to their baseline values after the initial decrease. Nevertheless, by Postoperative Day 1, both groups demonstrated the "sick" euthyroid syndrome and could not be distinguished from one another. This study demonstrates greater pituitary release of TSH in children undergoing repair of congenital heart defects with DHCA compared with CPB alone, the cause of which could not be determined in this study. However, despite the increase in TSH in the DHCA group, the thyroid hormone concentrations failed to increase appropriately. IMPLICATIONS: Early after deep hypothermia circulatory arrest, thyrotopin concentrations increase appropriately, responding to decreased concentrations of T3; however, all children undergoing cardiopulmonary bypass eventually develop a "sick" euthyroid syndrome by Postoperative Day 1. Whether this difference represents better protection of neuroendocrine function by deep hypothermic circulatory arrest (relative to cardiopulmonary bypass alone) remains speculative.

The response of patients with Duchenne's muscular dystrophy to neuromuscular blockade with vecuronium.

BACKGROUND: The authors hypothesized that patients with Duchenne's muscular dystrophy (DMD) are more sensitive to nondepolarizing muscle relaxants. METHODS: Eight children with DMD and eight healthy children having orthopedic procedures were studied. Anesthesia consisted of thiopental, 60% nitrous oxide in 40% oxygen, and intravenous fentanyl and midazolam. Using electromyography, the ulnar nerve was stimulated and the electromyographic train-of-four ratio (TOFr) of the first dorsal interosseous muscle was recorded every 60 s. After baseline TOFr recording, all patients received 50 microg/kg vecuronium and the TOFr at 3 min was compared. Vecuronium (10 microg/kg) was then administered every minute until TOFr was < or =0.1. The TOFr was followed until TOFr was > or =0.01. Then 10 microg/kg of vecuronium were administered to maintain TOFr < or = 0.1. At the conclusion of the procedure, TOFr was allowed to recover to 0.25, and then neostigmine and glycopyrrolate were administered. Data are presented as medians and ranges. RESULTS: The initial dose of vecuronium resulted in greater TOFr depression in patients with DMD than in controls (0.14 vs. 0.86). Less vecuronium was needed to produce TOFr < or = 0.1 in the patients with DMD than in the control patients (55 microg/kg vs. 95 microg/kg). Recovery time for the TOFr to > or =0.1 after the initial dose was longer in the patients with DMD than in the controls (28 vs. 20 min; P = 0.03), and the maintenance dose of vecuronium was less in patients with DMD (0.6 vs. 1.3 microg x kg[-1] min[-1]; P < 0.01). The time for TOFr recovery from 0.1 to 0.25 was 36 min in the patients with DMD and 6 min in the controls (P < 0.01). After neostigmine, the TOFr was 1.0 in the controls and 0.91 (P = 0.03) in the patients with DMD. CONCLUSION: There is increased sensitivity to vecuronium from neuromuscular blockade in patients with DMD.

Differential onset of median nerve block: randomized, double-blind comparison of mepivacaine and bupivacaine in healthy volunteers.

We have compared the delay in onset of 1% mepivacaine and 0.33% bupivacaine in different nerve fibre types in 10 volunteers undergoing median nerve blocks, in a randomized, double-blind, crossover study. Hot, cold, pinprick and light touch sensations, compound motor action potentials (CMAP), sensory nerve action potentials (SNAP) and skin temperature were recorded at 2-min intervals. Hot, cold, pinprick, light touch sensations, SNAP and CMAP were significantly inhibited, and skin temperature was significantly increased after administration of both agents. The first noticeable reduction in cold sensation was detected later after bupivacaine compared with mepivacaine, but after a delay similar to that of other nerve functions. Bupivacaine and mepivacaine inhibited SNAP and CMAP with a similar time delay to steady-state. Bupivacaine produced steady-state inhibition of hot and cold sensations significantly later than mepivacaine; nevertheless, the sequence that sensory modalities failed, with few exceptions, and the extent of anaesthesia at 40 min were similar for both agents. Our technique provides a novel, multi-modal method of comparing local anaesthetics and related agents over time.

Andersen's syndrome: a distinct periodic paralysis.

A previous study of 4 patients defined Andersen's syndrome (AS) as a triad of potassium-sensitive periodic paralysis, ventricular dysrhythmias, and dysmorphic features. AS appears to be distinct in terms of its genetic defect from the alpha-subunit of skeletal muscle sodium channel and the cardiac potassium channel responsible for most long QT syndromes (LQT1). We studied 11 additional patients with AS from 5 kindreds. Spontaneous attacks of paralysis were associated with hypokalemia, normokalemia, or hyperkalemia. All 11 patients had similar dysmorphic features. The QT interval was prolonged in all patients although only 4 were symptomatic. Genetic linkage studies excluded linkage to the alpha-subunit of the skeletal muscle sodium channel and to four distinct LQT loci. In addition, none of the common dihydropyridine receptor mutations responsible for hypokalemic periodic paralysis were present. We conclude that (1) AS is a genetically unique channelopathy affecting both cardiac and skeletal membrane excitability, (2) attacks of paralysis may be either hypokalemic or hyperkalemic, (3) a prolonged QT interval is an integral feature of this syndrome, and (4) a prolonged QT interval may be the only sign in an individual from an otherwise typical AS kindred. This may be confused with more common, potentially lethal LQT syndromes.

Unexpected interaction of methylphenidate (Ritalin) with anaesthetic agents.

We report difficulty with conscious sedation of a child taking methylphenidate for attention deficit disorder and possible delayed adverse interaction of ketamine and methylphenidate resulting in severe nausea, vomiting and dehydration. The effects of methylphenidate and its potential interactions with anaesthetic agents is discussed. We suggest that anaesthesiologists who provide sedation or anaesthesia to patients receiving methylphenidate be aware of the potential need for high sedative doses and the possibility of undesirable interactions.