Predictors of mortality in Ugandan children with TB, 2016-2021.

BACKGROUND: The burden of pediatric TB is high in Uganda. Our objective was to evaluate predictors of mortality during TB treatment among children at an urban and a rural referral hospital.METHODS: We designed a historical cohort study of TB cases at Mulago National Referral Hospital, Kampala; and Fort Portal Regional Referral Hospital, Fort Portal, Uganda, in children aged <15 years from 2016 to 2021. We used Kaplan-Meier models to estimate survival and fit multivariable Cox regression models to determine mortality hazards during TB treatment.RESULTS: We identified 1,658 children diagnosed with TB from 2016 to 2021. Of 1,623 children with known treatment outcomes, 127/1,623 (7.8%) died during TB treatment, 1,298/1,623 (78.3%) completed treatment, 150/1,623 (9.2%) were lost to follow-up, and two children failed treatment. Using Kaplan-Meier functions, the median time to death was 27 days following treatment initiation. In adjusted Cox models, predictors of mortality included HIV (aHR 1.68, 95% CI 1.01-2.81), moderate malnutrition (aHR 2.22, 95% CI 1.18-4.16), and severe malnutrition (aHR 2.92, 95% CI 1.75-4.87).CONCLUSION: Mortality was high at an urban and a rural referral hospital among children who initiated TB treatment from 2016 to 2021, with the majority of deaths occurring during the intensive phase of TB treatment. Malnutrition and HIV were significant predictors of death during treatment.

Antagonist-precipitated and discontinuation-induced withdrawal in morphine-dependent rhesus monkeys.

RATIONALE: Upon discontinuation of chronic opioid treatment, withdrawal typically peaks in 1-3 days and decreases markedly within 1 week; however, persistent physiological changes have been reported long after other signs have waned. OBJECTIVE: The goal of this study was to compare the discriminative stimulus, directly observable signs, and physiological effects of withdrawal in morphine-treated monkeys. MATERIALS AND METHODS: Monkeys received 5.6 mg/kg/12 h morphine and discriminated 0.0178 mg/kg naltrexone while responding under a fixed-ratio 5 schedule of stimulus-shock termination. Drug discrimination, behavioral observation, and telemetry were used to monitor the emergence of withdrawal, as well as any persistent changes, following discontinuation of morphine treatment. RESULTS: Naltrexone dose (0.001-0.032 mg/kg, s.c.) was positively related with indices of withdrawal. In the discrimination study, monkeys responded on the naltrexone lever 1-5 days following discontinuation of treatment; thereafter, they responded exclusively on the saline lever. After discontinuation of morphine, the frequency of observable signs peaked within 2-3 days and most were not significantly increased after 5 days. In contrast, increased heart rate and body temperature persisted for 14 days, returning to values obtained prior to discontinuation by 21 days. CONCLUSIONS: To the extent that discriminative stimulus effects of withdrawal in nonhumans are predictive of subjective reports of withdrawal in humans, these data indicate that effective treatments for opioid dependence must address not only the short-term subjective components of withdrawal but also, and perhaps more importantly, lingering behavioral and physiological effects that might contribute to relapse long after chronic drug use is discontinued.

Isoflurane preserves adenosine triphosphate levels in anoxic isolated rat hepatocytes by stimulating glycolytic adenosine triphosphate formation.

The hypothesis that general anesthetics protect energy reserves by decreasing energy demand is widely accepted but poorly substantiated. Isoflurane at clinical doses preserved adenosine triphosphate (ATP) levels in anoxic isolated hepatocytes. Specific inhibitors were used to block mitochondrial and/or glycolytic ATP formation to ascertain whether pathways of energy supply or demand, or both, were involved in ATP preservation by isoflurane. Hepatocytes were isolated from fed adult male rats after perfusing livers with Krebs buffer containing collagenase. Cells were incubated in Krebs buffer for 0-30 min at 25 degrees C under N2/CO2 (95%/5%) +/- isoflurane 0.63 mM in liquid phase. Oligomycin, iodoacetate, or fasting were used to block mitochondrial and glycolytic ATP formation. Under anoxia alone, ATP levels declined more slowly in the presence than in the absence of isoflurane, confirming the ATP-protective effect of isoflurane reported previously. With oligomycin plus iodoacetate blocking all ATP formation, ATP decline (representing pure ATP consumption) was not slowed by isoflurane. Isoflurane's protective effect recurred when glycolytic ATP supply was restored by incubating with oligomycin only. The protective effect was accompanied by increased lactate accumulation, and both effects-ATP preservation and lactate formation-were similarly dependent on isoflurane concentration. We conclude that the protective effect of isoflurane on energy status in anoxic isolated hepatocytes was not associated with reduced ATP demand but with enhanced ATP supply via stimulation of glycolysis.

Energy status in anoxic rat hepatocytes: effects of isoflurane, solution composition, and hypothermia.

Both cold and warm ischemia occur during liver transplantation. Hypothermia and Wisconsin solution preserve adenine nucleotide energy status, which is crucial to hepatic function and viability. The volatile anesthetic isoflurane has been shown to preserve energy status in anoxic isolated hepatocytes in warm Krebs solution. The present study examined isoflurane effects on energy status during incubation also in Wisconsin or Krebs-plus-adenosine solution at 37 degrees or 4 degrees. Hepatocytes were isolated from rat liver after perfusion with Krebs + collagenase. In 25-mL flasks, 12.5 million cells in 2.5 mL of Krebs, Krebs plus 5 mmol/L adenosine, or Wisconsin solution were incubated under an atmosphere of O2/CO2 or N2/CO2 (19:1) +/- isoflurane (3 volumes% = 2ED50), for 30 minutes at 37 degrees C or 4 degrees C. Adenine nucleotides were measured by high-performance liquid chromatography (HPLC), lactate enzymatically. During warm (37 degrees) anoxia, Wisconsin solution preserved energy status; Krebs plus adenosine did not. Isoflurane further protected energy status in all three solutions. Hypothermia (4 degrees) alone greatly decreased anoxic loss of energy status in all solutions. In Wisconsin solution only, energy status tended to be higher in anoxic than in oxygenated cells and was further enhanced by isoflurane, with corresponding increases in lactate. During 30 minutes of either warm or cold anoxia, isoflurane and Wisconsin solution each helped preserve adenine nucleotide energy status in isolated hepatocytes, at least in part through enhanced glycolysis.

Effects of subcutaneous verapamil on the duration of local anesthetic blockade.

STUDY OBJECTIVES: To determine whether a subcutaneous injection of verapamil will provide local anesthesia and whether a mixture of lidocaine and verapamil will prolong the anesthetic effect of lidocaine alone. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Preanesthetic area of a large metropolitan teaching hospital. PATIENTS: 20 volunteers. INTERVENTIONS: All volunteers received 4 injections of normal saline, verapamil, lidocaine, and lidocaine-verapamil at the volar aspect of the forearm. The sites were tested with a 26-gauge needle to be sure the sensation of sharp could be appreciated. The injections were performed in a randomized, double-blind fashion using a sterile technique. The 4 areas were tested at 1-minute intervals using a 26-gauge needle until the sensation of sharp was again perceived. MEASUREMENTS AND MAIN RESULTS: Injection sites were examined for the presence and degree of erythema. Volunteers were asked to rate the degree of pain felt during and immediately after injection. The time elapsed until the person was again able to perceive sharp from a 26-gauge needle prick was measured at all 4 sites. When compared with the effects of normal saline, subcutaneous verapamil provided local anesthesia to pinprick. The mixture of verapamil and lidocaine also provided anesthesia to pinprick, but the duration of effect was less than that provided by lidocaine alone. The use of verapamil alone and in combination with lidocaine was associated with a marked degree of erythema and edema. CONCLUSIONS: Verapamil injected subcutaneously provides a degree of local anesthesia. However, this effect is hampered by a local reaction at the injection site and a short duration of action. The mixture of lidocaine and verapamil provides a shorter duration of action than does lidocaine alone.

Isoflurane isomers differ in preservation of ATP in anoxic rat hepatocytes.

The volatile anesthetic isoflurane inhibits the precipitous drop of ATP concentration that results from induced anoxia in isolated rat hepatocytes. This change is dose dependent and reaches its maximum at clinically relevant anesthetic concentrations. The use of highly purified isoflurane enantiomers has allowed a demonstration of the difference in the efficacy of the (+) and (-) isomers on the isoflurane-dependent preservation of ATP. The difference in relative potency between isomers was approximately 2.5-fold, with the (-) form being more potent. In a direct test of the anesthetic potency of these isomers, it was shown previously that the (+) isomer was more potent than the (-) isomer. Differences in the order of potency of isoflurane stereoisomers for the "anesthetic" and "metabolic" effects of isoflurane suggest that these effects are independent and may result from interactions with different specific molecular sites.

Effects of isoflurane dose, duration of anoxia, and reoxygenation on isoflurane's preservation of energy balance in anoxic isolated hepatocytes.

We investigated how the protection of energy status by isoflurane in isolated hepatocytes varied with isoflurane dose, duration of anoxia, and reoxygenation. Hepatocytes were isolated from fed rats and incubated in Krebs buffer under O2/CO2 or N2/CO2 (95/5) for 30 or 90 min, followed by 5 or 30 min of reoxygenation. From measurements of adenosine tri-, di-, and monophosphate (ATP, ADP, AMP) in the cells, energy charge (= [ATP + 1/2 ADP]/[ATP + ADP + AMP]) was calculated to reflect the balance between ATP supply and demand, and total adenine nucleotide (= ATP + ADP + AMP) to indicate the potential maximum ATP level. During 30 min of anoxia, energy charge and total adenine nucleotide steadily increased with isoflurane dose from 0 to 2 minimum alveolar anesthetic concentration, then decreased from 2 to 3 minimum alveolar anesthetic concentration. In short incubations (30-35 min) at 1 minimum alveolar anesthetic concentration isoflurane, there was a modest decrease in energy charge during anoxia, partially prevented by isoflurane and completely reversed by reoxygenation, and no decrease in total adenine nucleotide. In long incubations (90-120 min), there were large decreases in both energy charge and total adenine nucleotide during anoxia, with partial and no reversal by reoxygenation, respectively. Isoflurane partly prevented decreases in both energy charge and total adenine nucleotide during both anoxia and reoxygenation. We conclude that at doses in the clinical range, isoflurane partially protected isolated hepatocytes against decreases in both energy charge and total adenine nucleotide occurring either during short (reversible) or long (irreversible) anoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma laudanosine levels in patients given atracurium during liver transplantation.

Atracurium, a nondepolarizing muscle relaxant, does not depend on the liver for clearance, but its principal metabolite, laudanosine, is eliminated primarily by the liver and is potentially neurotoxic. We measured atracurium and laudanosine levels in 15 adult patients during the three stages of liver transplantation to assess the effect of major impairment of liver function. Atracurium was given in a bolus dose of 0.5 mg/kg followed by continuous infusion at a rate adjusted to maintain 95-99% of total neuromuscular block, as judged by train of four response to facial nerve stimulation. Atracurium levels remained constant at 1.4-1.8 micrograms/mL during the 180-min preanhepatic and 75-min anhepatic stages but decreased to a mean of 1.0 microgram/mL by the end of the 180-min postanhepatic stage. In contrast, laudanosine levels increased during each stage, being 0.40 +/- 0.18, 0.50 +/- 0.22, and 0.43 +/- 0.16 micrograms/mL after the preanhepatic, anhepatic, and postanhepatic stages, respectively. The highest individual value recorded was 1.02 microgram/mL. We conclude that, despite increases in laudanosine levels during each stage of liver transplantation in patients receiving atracurium, those levels are only about one-tenth of the maximum values previously reported in humans.

Oral clonidine blunts the hemodynamic responses to brief but not prolonged laryngoscopy.

STUDY OBJECTIVE: To determine whether a 300 micrograms dose of oral clonidine given 90 minutes prior to laryngoscopy and intubation provides hemodynamic protection from the stress of a brief (15-second) and/or a prolonged (45-second) laryngoscopy. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Inpatients and outpatients scheduled for general anesthesia with intubation at a university-affiliated medical center. PATIENTS: Forty patients who gave informed, written consent to receive either an oral placebo or clonidine 5 micrograms/kg (up to a maximum dose of 300 micrograms) 90 minutes prior to induction of anesthesia and to undergo either brief or prolonged laryngoscopy prior to intubation. INTERVENTIONS: The patients underwent a standardized induction sequence that included d-tubocurarine 3 mg, thiopental sodium 5 mg/kg, and succinylcholine 1.5 mg/kg. The four treatment groups (each n = 10) included (1) placebo with 15-second laryngoscopy, (2) placebo with 45-second laryngoscopy, (3) clonidine with 15-second laryngoscopy, and (4) clonidine with 45-second laryngoscopy. Heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were mechanically obtained and recorded at 1-minute intervals for 12 minutes. MEASUREMENTS AND MAIN RESULTS: There were no differences between groups in the premedication hemodynamic measurements. Within each group, maximal hemodynamic variables increased significantly over the corresponding baseline values for that group. In the 15-second, but not the 45-second, laryngoscopy, clonidine successfully blunted the maximum SBP and DBP obtained when compared with the corresponding control group. In both the 15- and 45-second clonidine groups, maximum HR was significantly lower than in the corresponding placebo groups. CONCLUSIONS: Oral clonidine, when used as a preoperative medication, affords hemodynamic protection to patients undergoing a 15-second laryngoscopy. However, the stress of a 45-second laryngoscopy may be too great or the 300 micrograms dose of clonidine too low to provide hemodynamic protection for patients in this group.

Lecture practices in United States anesthesiology residencies.

We obtained data on lecture practices from 100 of the 110 university-affiliated anesthesiology residency programs certified in the United States in 1988. Of these residency programs, 36% had a majority of their lectures before the operating room schedule began, 57% had no lectures at all in this early time slot, and 78% had morning lectures at least once a week in conjunction with a delayed operating room start. Seventy-one percent of programs had one or more afternoon lectures each week. An attendance of more than 80% was reported in 66% of the programs for morning lectures and in 50% of the programs for afternoon lectures, which is a significant difference. Aggregate pass rates on the American Board of Anesthesiology written examinations in 1987 and 1988 correlated significantly with morning-lecture attendance, but not with afternoon-lecture attendance, number of lecture days per week, or mandatory lecture attendance. These findings suggest the need for further study and definition of the role of lectures in resident education in anesthesiology.

The effectiveness of oral clonidine as a sedative/anxiolytic and as a drug to blunt the hemodynamic responses to laryngoscopy.

STUDY OBJECTIVE: To determine the effects of oral clonidine premedication on sedative, anxiolytic, and hemodynamic responses during the immediate preoperative period, laryngoscopy/intubation, and postanesthetic recovery. DESIGN: Randomized double-blind assignment to one of four treatment groups (clonidine 0.1 mg, clonidine 0.2 mg, triazolam 0.25 mg, or placebo); n = 10 per group. SETTING: Inpatient surgery in a university-staffed tertiary center. PATIENTS: Forty ASA physical status I and II adults of both sexes scheduled for a variety of procedures requiring general anesthesia. INTERVENTIONS: Anxiety and sedation scored on ordinal scale at time of treatment and 90 minutes later, just prior to anesthetic induction. Standardized induction protocol with automated hemodynamic monitoring at 1-minute intervals and a 45-second laryngoscopy to ensure a vigorous stress response. MEASUREMENTS AND MAIN RESULTS: Triazolam and both doses of clonidine increased sedation at 90 minutes both absolutely and compared with a placebo. Clonidine 0.2 mg decreased anxiety absolutely at 90 minutes but no more than a placebo. Clonidine 0.2 mg decreased systolic, mean, and diastolic blood pressures (BPs) but not heart rate (HR) at 90 minutes. Clonidine 0.2 mg also blunted the increase in systolic blood pressure (SP) [but not in diastolic blood pressure (DP) or HR] that accompanied laryngoscopy. There were no treatment differences in postanesthetic hemodynamics or duration of recovery. CONCLUSIONS: Oral clonidine 0.2 mg was effective in reducing the level of behavioral and hemodynamic responses preoperatively and in blunting systolic hypertension produced by prolonged laryngoscopy.

Atracurium use in a patient with familial periodic paralysis.

We describe a patient with the hypokalemic type of familial periodic paralysis (FPP) who received atracurium for muscle relaxation as required for diagnostic laparoscopy. Electrocardiographic (EKG) T-wave changes suggestive of hypokalemia were not supported by blood determinations. Arterial blood measurements of potassium (K+), pH, and arterial carbon dioxide tension (PaCO2) and the patient's esophageal temperature were maintained within normal limits. The degree of muscle relaxation was closely monitored by a peripheral nerve stimulator and train-of-four (TOF) measurement of muscle twitch height. At the conclusion of the surgical procedure, no reversal to the muscle relaxant was needed or given. The patient regained preoperative muscle strength, and her postoperative course was uneventful.

Isoflurane partially preserves energy balance in isolated hepatocytes during in vitro anoxia.

We investigated whether a volatile anesthetic (1.5% isoflurane or 1.0% halothane) or an added anaerobic energy source (10 mM glucose or fructose) could act directly on liver cells to protect energy status during 20-30 min of anoxia. We used hepatocytes freshly isolated from fed rats or rats that had fasted, suspended them in Krebs' buffer, and incubated them in sealed flasks under O2/CO2 or N2/CO2 (95%:5%). The adenosine triphosphate (ATP) to adenosine diphosphate (ADP) ratio (ATP/ADP) measured cellular energy balance--the balance between overall ATP supply and demand. Lactate levels measured the extent to which ATP was supplied by the nonmitochondrial pathway, (anaerobic) glycolysis. Maximum values of energy balance were seen in cells from fed rats incubated in the presence of glucose and O2. When glucose was replaced by fructose, ATP/ADP decreased and lactate increased. During anoxia (O2 replaced by N2), increases in lactate were also seen with glucose; and ATP/ADP decreased to similarly low values with both substrates. In cells from fasted rats, ATP/ADP decreased significantly below the value for cells from fed rats only in the presence of glucose and O2. Compared with cells from fed rats, cells from fasted rats showed decreased lactate in the face of decreased ATP/ADP, suggesting that glycolysis was impaired. Isoflurane partially prevented anoxia-induced decreases in ATP/ADP. This protective effect on energy balance occurred equally with glucose and fructose, but was not seen in cells from fasted rats or with halothane. Thus, 1 MAC isoflurane and some factor(s) related to the fed state combined to protect partially the energy balance in anoxic liver cells through action(s) at the cellular level.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia for glucagonoma resection.

Anesthetic experience with three cases of the resection of glucagonoma, a rare tumor of alpha cells of pancreatic islets, is presented. Marked increases of blood glucagon and glucose levels, with the potential for clinically significant metabolic and myocardial dysfunction, did not occur during anesthesia and surgery. Associated tumors of other endocrine cell types also were absent in the three study patients. Strategies for anticipating and managing other perioperative problems associated with glucagonoma also are discussed.

Ischemic brain injury in vitro: protective effects of NMDA receptor antagonists and calmidazolium.

Excessive Ca2+ influx through NMDA receptor-coupled channels has been linked to neuronal cell death. Using an in vitro model of transient brain ischemia, we investigated possible protective effects of NMDA receptor antagonists ketamine or MK-801 and of calmidazolium, an inhibitor of intracellular Ca2(+)-activated proteins. Brain ischemia/recovery was simulated in isolated hippocampal slices and injury monitored by measurement of ATP levels. Omission of both glucose and oxygen (but not oxygen alone) for 20 min led to persistent ATP deficits after 4 h recovery. Addition of ketamine or MK-801 at 1 microM permitted ATP to recover within 1 h, as did addition of calmidazolium at 10 microM. Our findings are consistent with other reports that NMDA receptor antagonists can protect neuronal tissue from ischemic damage. The role of inappropriately activated Ca2(+)-mediated signaling processes in the mechanism(s) of such injury is suggested by the protection also seen with calmidazolium, an inhibitor of calmodulin and other structurally related proteins such as calpain(s) and protein kinase C. The inhibition of intracellular Ca2+ target proteins may be an alternative for protection of the brain against injury due to insults that activate NMDA receptors.

Obligate mouth breathing during exercise. Nasal and laryngeal sarcoidosis.

A young black man presented with simultaneous nasal and laryngeal sarcoidosis, each uncommon entities. Despite severe upper airway obstruction and emergent tracheostomy, there was an uncharacteristic rapid response to oral steroids alone. The patient's predominant initial complaint of early mouth breathing during routine army physical training demonstrates a symptom complex and an alternate mechanism of dyspnea to consider in sarcoidosis.