Effect of ventilation on cerebral oxygenation in patients undergoing surgery in the beach chair position: a randomized controlled trial.

BACKGROUND: Surgery in the beach chair position (BCP) may reduce cerebral blood flow and oxygenation, resulting in neurological injuries. The authors tested the hypothesis that a ventilation strategy designed to achieve end-tidal carbon dioxide (E'(CO2)) values of 40-42 mm Hg would increase cerebral oxygenation (Sct(O2)) during BCP shoulder surgery compared with a ventilation strategy designed to achieve E'(CO2) values of 30-32 mm Hg. METHODS: Seventy patients undergoing shoulder surgery in the BCP with general anaesthesia were enrolled in this randomized controlled trial. Mechanical ventilation was adjusted to maintain an E'(CO2) of 30-32 mm Hg in the control group and an E'(CO2) of 40-42 mm Hg in the study group. Cerebral oxygenation was monitored continuously in the operating theatre using near-infrared spectroscopy. Baseline haemodynamics and Sct(O2) were obtained before induction of anaesthesia, and these values were then measured and recorded continuously from induction of anaesthesia until tracheal extubation. The number of cerebral desaturation events (CDEs) (defined as a ≥20% reduction in Sct(O2) from baseline values) was recorded. RESULTS: No significant differences between the groups were observed in haemodynamic variables or phenylephrine interventions during the surgical procedure. Sct(O2) values were significantly higher in the study 40-42 group throughout the intraoperative period (P<0.01). In addition, the incidence of CDEs was lower in the study 40-42 group (8.8%) compared with the control 30-32 group (55.6%, P<0.0001). CONCLUSIONS: Cerebral oxygenation is significantly improved during BCP surgery when ventilation is adjusted to maintain E'(CO2) at 40-42 mm Hg compared with 30-32 mm Hg. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01546636.

Human skin Langerhans cells are targets of dengue virus infection.

Dengue virus (DV), an arthropod-borne flavivirus, causes a febrile illness for which there is no antiviral treatment and no vaccine. Macrophages are important in dengue pathogenesis; however, the initial target cell for DV infection remains unknown. As DV is introduced into human skin by mosquitoes of the genus Aedes, we undertook experiments to determine whether human dendritic cells (DCs) were permissive for the growth of DV. Initial experiments demonstrated that blood-derived DCs were 10-fold more permissive for DV infection than were monocytes or macrophages. We confirmed this with human skin DCs (Langerhans cells and dermal/interstitial DCs). Using cadaveric human skin explants, we exposed skin DCs to DV ex vivo. Of the human leukocyte antigen DR-positive DCs that migrated from the skin, emigrants from both dermis and epidermis, 60-80% expressed DV antigens. These observations were supported by histologic findings from the skin rash of a human subject who received an attenuated tetravalent dengue vaccine. Immunohistochemistry of the skin showed CD1a-positive DCs double-labeled with an antibody against DV envelope glycoprotein. These data demonstrate that human skin DCs are permissive for DV infection, and provide a potential mechanism for the transmission of DV into human skin.

Falciparum malaria.

Falciparum malaria is one of the most common infectious illnesses in the world and can progress rapidly to coma and death in the nonimmune patient. The presentation is nonspecific, so blood smears must be made and read quickly. Proper therapy requires taking into account drug resistance, recognizing the signs of severe malaria, and proper treatment for complications. Long-sleeved clothing, bed nets, insecticides, and chemoprophylaxis can help prevent malaria, but the infection must be suspected in any traveler returning from an endemic area. This article reviews epidemiology, diagnosis, treatment, and prevention of falciparum malaria in the temperate zone.

Short report: Antibody responses of mice immunized with a tetravalent dengue recombinant protein subunit vaccine.

Recombinant proteins containing the B domain of dengue virus serotypes 1-4 fused to the maltose binding protein (MBP) of Escherichia coli were evaluated individually and as a tetravalent vaccine candidate in mice. Sera from mice immunized with monovalent DEN-MBP recombinant protein vaccines developed high titers of serotype homologous antibody in the enzyme-linked immunosorbent assay and the plaque-reduction neutralization test. Cross-reactive antibody titers were either several dilutions lower or not detectable. Sera from mice immunized with the tetravalent DEN subunit vaccine neutralized all 4 DEN viruses in the plaque-reduction neutralization test. The neutralizing antibody titers to each individual serotype were significantly greater than any cross-reactive neutralizing antibody titers induced by the monovalent vaccines, providing evidence that the tetravalent DEN recombinant subunit vaccine produced specific neutralizing antibody to all 4 serotypes of dengue virus.

Characterization of antibody responses to combinations of a dengue-2 DNA and dengue-2 recombinant subunit vaccine.

A dengue-2 (DEN-2) DNA vaccine coding for the premembrane and envelope (E) proteins and a recombinant fusion protein containing the B domain of the DEN-2 E protein fused to the maltose-binding protein (MBP) of Escherichia coli both elicited neutralizing antibody in mice. In order to achieve more rapid protective immunity as well as to increase the persistence of neutralizing antibody, we primed mice with the DNA vaccine (D), the recombinant MBP protein (R), or both (RD) given simultaneously, and then boosted twice with either the R (R/R/R or D/R/R) or D (D/D/D or R/D/D) constructs alone or the RD (RD/RD/RD) combination. All of the recombinant protein vaccines were given with alum as an adjuvant. The serum antibody response measured by enzyme-linked immunosorbent assay was highest in D/D/D mice and RD/RD/RD mice. The D/R/R mice showed an intermediate response, and the R/D/D and R/R/R showed the lowest response. The geometric mean (GM) 50% neutralizationtiter (50% plaque reduction neutralization, or PRNT50) was marginally higher for RD/RD/RD mice (891) at 9 months after priming than that for R/R/R mice (724). T he lowest GM PRNT50 titers were seen in the D/D/D mice (33) and R/D/D mice (40), and the D/R/R group had a slightly higher titer (156) than these 2 groups. The predominant antibody subclass for the D/D/D mice was immunoglobulin (Ig) G2a, similar to mice infected with live virus. The R/R/R mice showed an exclusive IgGI antibody response, and the RD/RD/RD response also was predominantly IgGI. The antibody subclass pattern of the R/D/D and D/R/R mice showed a more balanced distribution of both IgG1 and IgG2a. Investigating the neutralizing capacity of antibody subclasses suggested that both IgG1 and IgG2a could neutralize DEN-2 virus. Our observations indicate that the combination RD prime-boost regimen warrants further investigation as a vaccine strategy to prevent dengue infection.

Neuromuscular-blocking drugs. Use and misuse in the intensive care unit.

The use of NMB agents for more than 24 to 48 hours in critically ill patients is associated with many potential complications. Neuromuscular-blocking drugs should be used only when their use is essential for optimal patient care. The indications for neuromuscular blockade must be defined clearly, and patients should be evaluated during treatment for the need for continued muscle relaxation. The smallest doses of NMB agents that will accomplish clinical goals should be used. This dosage can be determined through clinical evaluations and peripheral nerve monitoring. It is essential that all patients treated with NMB drugs receive appropriate sedation and analgesia. Myopathies, neuropathies, and alterations of the neuromuscular junction can occur in the ICU setting, and nondepolarizing muscle relaxants seem to be involved in the development of these disorders. Clinicians should be aware of risk factors that may predispose certain patients to neuromuscular complications, including sepsis and the use of high-dose steroids. Neuromuscular-blocking agents should be avoided in these patients if possible. Although not proved, early recognition and treatment of iatrogenic neuromuscular complications may improve patient outcome.

The effect of a new NPO policy on operating room utilization.

STUDY OBJECTIVES: To prospectively assess the impact of a liberalized preoperative fasting policy on operating room (OR) utilization. STUDY DESIGN: Prospective cohort study involving data collection before and after a change in nil per os (NPO) policy. SETTING: Academic teaching hospital. PATIENTS: 5,420 consecutive outpatients and AM admissions. INTERVENTIONS: Data collection was done on all adult patients who presented to our OR suite over two 15-week periods. During the first 15-week period, patients were instructed to drink no liquids after midnight (control group, n = 2,646). In the second 15-week period, patients were allowed to consume unlimited clear fluids until 2 to 3 hours prior to surgery (study group, n = 2,774). MEASUREMENTS AND MAIN RESULTS: We found no difference between the control and study groups in the number of cases cancelled (0 in each group) or delayed (8 vs. 9; relative risk [RR] = 1.07, 95% confidence interval [CI] = 1.000 to 1.148) due to noncompliance with fasting guidelines. There was no difference between the groups in the number of cases of aspiration (0 in each group). In the control group, significantly more episodes of regurgitation were noted (12 vs. 9; RR = 0.715, 95% CI = 0.535 to 0.955) and more rapid-sequence/awake intubations were performed (119 vs. 51; RR = 0.409, 95% CI = 0.306 to 0.546) than in the study group. CONCLUSIONS: Liberalizing a preoperative fasting policy and allowing patients to consume unrestricted clear fluids up until 3 hours before their scheduled time of surgery did not affect their compliance with fasting requirements. No increase in cancellations or delays of surgical procedures due to inappropriate oral intake was observed.

Residual neuromuscular blockade: incidence, assessment, and relevance in the postoperative period.

The residual effects of neuromuscular blocking agents may persist into the early postoperative recovery period, even when neuromuscular blockade is carefully monitored and reversed in the operating room. Recent data suggest that mild degrees of residual paresis (train-of-four TOF ratios of 0.7-0.9) may be associated with significant impairment of respiratory and pharyngeal muscle function. Therefore, the new gold standard reflecting acceptable neuromuscular recovery is a TOF ratio > or =0.9. Several investigations have demonstrated that many patients continue to arrive in the postanesthesia care unit with TOF ratios <0.7-0.9. Several techniques may be used to reduce the risk of postoperative residual paresis, which include avoidance of long-acting muscle relaxants, use of neuromuscular monitoring in the operating room, routine reversal of neuromuscular blockade at a TOF count of 2-3, and early administration of reversal agents. Careful management of neuromuscular blockade may limit the occurrence of adverse events associated with residual postoperative paralysis. Large-scale outcome studies are needed to clearly define the impact of residual neuromuscular block on major morbidity and mortality in surgical patients.

Treatment of gastrointestinal infections.

During the past year, we have seen the continuing spread of antimicrobial drug resistance in important gastrointestinal pathogens. Typhoid fever seen in the United States was multidrug resistant, but still susceptible to quinolones. The mechanism of quinolone resistant typhoid in Vietnam was better elucidated. Treatment failures in enterobacteriaceae treated with quinolones suggest that the minimum inhibitory concentration break point for resistance should be lowered. Evidence is mounting that ciprofloxacin and ofloxacin may be safely used to treat serious infections in children. Cefixime showed some promise in treating shigellosis in an open labeled trial. Decreased gastric acid secretion was associated with cholera but not dysentery. Phase 1 trials of vaccines for cholera and enterotoxigenic Escherichia coli showed promise. The antifungal drug, clotrimazole, demonstrated ability to inhibit secretory diarrhea in laboratory studies. Nitazoxanide demonstrated efficacy in both protozoan and helminthic infections in humans, including fascioliasis.

Detection of Shigellae and enteroinvasive Escherichia coli by amplification of the invasion plasmid antigen H DNA sequence in patients with dysentery.

Detection of Shigella organisms and enteroinvasive Escherichia coli (EIEC) by polymerase chain reaction (PCR) was evaluated in 20 patients with dysentery before and in 17 of the 20 after treatment with ciprofloxacin. DNA sequences coding for IpaH antigen, a multiple copy sequence found on the chromosome, and the invasion plasmid locus (ial) was detected after DNA amplification in 13 stools from patients from whom shigellae or EIEC were isolated but not in 21 nondysenteric stools containing other enteric bacteria. Although shigellae or EIEC were not isolated from any patient with dysentery after ciprofloxacin treatment, IpaH and ial sequences were found after PCR amplification in 7 patients after treatment with ciprofloxacin. IpaH sequences alone were detected in 4 patients; DNA augmentation of IpaH in stools in a specific way to identify Shigella or EIEC infection in persons from whom cultures cannot be obtained promptly after the onset of diarrhea or who have received antibiotics.

Anaesthetic management of a parturient with myocardial infarction related to cocaine use.

Cocaine abuse is common among parturients with an incidence of 11.8 to 20%. Myocardial infarction is a rare and lethal event during pregnancy with an incidence of 1 in 10,000 pregnancies. We present the anaesthetic management of a parturient of 36 wk gestation who suffered a myocardial infarction nine hours before delivery which was temporally related to "crack" cocaine use. The patient's cardiovascular system became unstable following cocaine use, and she required mechanical ventilatory support and pharmacologic stabilization guided by invasive haemodynamic monitoring. This patient survived a non-Q wave myocardial infarction, but the prognosis of peripartum myocardial infarction remains poor with a mortality rate of 30-40% which is increased if the infarction occurs in the third trimester or postpartum period. The optimal mode and timing of delivery after myocardial infarction is unresolved. The association between cocaine use and myocardial infarction was first described in 1982, and cocaine remains unique among local anaesthetics in its ability to compromise the cardiovascular system through both sympathomimetic effects and vasoconstrictive effects on coronary arteries. Because of the prevalence of substance abuse, cocaine use should be considered in the differential diagnosis of sudden cardiovascular compromise in parturients.

Ciprofloxacin and loperamide in the treatment of bacillary dysentery.

OBJECTIVE: To compare the safety and efficacy of loperamide plus ciprofloxacin with those of ciprofloxacin alone in the treatment of bacillary dysentery. DESIGN: Double-blind, placebo-controlled, randomized clinical trial. SETTING: Hospital in Thailand. PARTICIPANTS: Eighty-eight adults with dysentery seeking medical care between November 1990 and February 1992. Patients who had received prior antibiotics or antimotility drugs were excluded. INTERVENTION: All 88 patients with dysentery were treated with ciprofloxacin, 500 mg twice daily for 3 days. Forty-two of these patients were randomly assigned to receive loperamide, a 4-mg initial dose followed by 2 mg after every loose stool (as many as eight caplets [16 mg] daily), and 46 were randomly assigned to receive placebo. MEASUREMENTS: Stools were collected daily until resolution of diarrhea and again after 10 days. The time to passage of the last unformed stool, number of unformed stools, and symptoms were recorded after treatment. RESULTS: Shigella or enteroinvasive Escherichia coli (53%), Vibrio parahaemolyticus (16%), and Salmonella (7%) were the most common bacterial enteric pathogens identified in 88 patients with dysentery. In patients infected with Shigella or enteroinvasive E. coli, the median duration of diarrhea was 19 hours (25th to 75th percentiles, 6 to 42 hours) for those receiving loperamide plus ciprofloxacin compared with 42 hours (21 to 46 hours) for those receiving ciprofloxacin alone (P = 0.028). The median number of diarrheal stools for those receiving ciprofloxacin and loperamide was 2.0 (1 to 5 stools) compared with 6.5 (2 to 9 stools) for those receiving ciprofloxacin alone (P = 0.016). None of the participants had a temperature greater than 38 degrees C after 24 hours of treatment. None of the patients was infected with the same bacterial enteric pathogen more than 1 day after receiving treatment. CONCLUSIONS: Loperamide decreases the number of unformed stools and shortens the duration of diarrhea in dysentery caused by Shigella in adults treated with ciprofloxacin.

Influence of a vital capacity maneuver on pulmonary gas exchange after cardiopulmonary bypass.

OBJECTIVE: To investigate the effect of a single, vital capacity breath (vital capacity maneuver [VCM]), administered at the end of cardiopulmonary bypass (CPB), on pulmonary gas exchange in patients undergoing coronary artery bypass graft surgery. DESIGN: Prospective, randomized, double-blind study. SETTING: University-affiliated hospital. PARTICIPANTS: Forty patients scheduled for elective coronary artery bypass graft surgery and early tracheal extubation. INTERVENTIONS: Patients were randomized to 1 of 2 groups. VCM patients received a VCM at the conclusion of CPB. Control patients received no VCM. MEASUREMENTS AND MAIN RESULTS: Intrapulmonary shunt (Q(S)/Q(T)), arterial oxygenation (PaO2), and alveolar-arterial oxygen gradients (P(A-a)O2) were measured after induction of anesthesia, CPB, intensive care unit (ICU) arrival, and extubation. The duration of postoperative intubation was recorded for each group. Q(S)/Q(T) increased significantly 30 minutes after CPB in the control group (15.7 +/- 1.8% to 27.4 +/- 2.6%; p = 0.01). In the VCM group, a small decrease in Q(S)/Q(T) occurred (16.1 +/- 2.0% to 14.9 +/- 2.0%). After ICU arrival and extubation, no significant difference in Q(S)/Q(T) existed between the 2 groups. With the exception of a higher P(A-a)O2 in the control group at induction of anesthesia, no differences in PaO2 or P(A-a)O2 were present between the 2 groups at any measurement interval. Patients who received a VCM were extubated earlier than the control group (6.5 +/- 2.1 hours v 9.4 +/- 4.2 hours; p = 0.01). CONCLUSION: The use of a VCM prevented an increase in Q(S)/Q(T) from occurring in the operating room. Although a VCM did not influence pulmonary gas exchange in the ICU, its application in the operating room appears to exert a beneficial effect on tracheal extubation times after cardiac surgery.

Dengue virus type 1 DNA vaccine induces protective immune responses in rhesus macaques.

A candidate DNA vaccine expressing dengue virus type 1 pre-membrane and envelope proteins was used to immunize rhesus macaques. Monkeys were immunized intramuscularly (i.m.) or intradermally (i.d.) by three or four 1 mg doses of vaccine, respectively. Monkeys that were inoculated i.m. seroconverted more quickly and had higher antibody levels than those that were inoculated i.d. The sera exhibited virus-neutralizing activity, which declined over time. Four of the eight i.m.-inoculated monkeys were protected completely from developing viraemia when challenged 4 months after the last dose with homologous dengue virus. The other four monkeys had reduced viraemia compared with the control immunized monkeys. The i.d. -inoculated monkeys showed no reduction in viraemia when challenged with the virus. All vaccinated monkeys showed an anamnestic antibody response, indicating that they had established immunological memory. Vaccine-induced antibody had an avidity index similar to that of antibody induced by virus infection; however, no clear correlation was apparent between antibody avidity and virus neutralization titres.

Synergistic neutralizing antibody response to a dengue virus type 2 DNA vaccine by incorporation of lysosome-associated membrane protein sequences and use of plasmid expressing GM-CSF.

We have previously shown that a dengue virus type 1 DNA vaccine expressing premembrane (prM) and envelope (E) genes was immunogenic in mice and monkeys and that rhesus monkeys vaccinated with this construct were completely to partially protected from virus challenge. In order to improve the immunogenicity of dengue DNA vaccines, we have evaluated the effect of lysosome targeting of antigens and coimmunization with a plasmid expressing GM-CSF on antibody responses. A dengue virus type 2 candidate vaccine containing prM and E genes was constructed in which the transmembrane and cytoplasmic regions of E were replaced by those of the lysosome-associated membrane protein (LAMP). The modified vaccine construct expressed antigen that was colocalized with endogenous LAMP in lysosomal vesicles of transfected cells, whereas the antigen expressed from the unmodified construct was not. It was hypothesized that targeting of antigen to the lysosomal compartment will increase antigen presentation by MHC class II, leading to stronger CD4-mediated immune responses. Mice immunized with the modified construct responded with significantly higher levels of virus neutralizing antibodies compared to those immunized with the unmodified construct. Coimmunization of mice with a plasmid expressing murine GM-CSF enhanced the antibody response obtained with either the unmodified or the modified construct alone. The highest antibody responses were noted when the modified construct was coinjected with plasmid expressing the GM-CSF gene. These results could form the basis for an effective tetravalent dengue virus DNA vaccine.

Comparison of two rapid diagnostic assays for detection of immunoglobulin M antibodies to dengue virus.

Two easy-to-use commercial diagnostic assays, a dipstick enzyme-linked immunosorbent assay (ELISA) (Integrated Diagnostics, Baltimore, Md.) and an immunochromatographic card assay (PanBio, Brisbane, Australia) were evaluated for detection of immunoglobulin M (IgM) antibody to dengue virus with an in-house IgM antibody capture microplate ELISA as a reference assay. The dipstick ELISA was based on the indirect-ELISA format using dengue 2 virus as the only antigen and enzyme-labeled goat anti-human IgM antibody as the detector. The total assay time was 75 min. The immunochromatographic card assay was based on the antibody capture format and separately measured both anti-dengue virus IgM and IgG in the same test. Colloidal-gold-labeled anti-dengue virus monoclonal antibody bound with dengue virus 1 to 4 antigen cocktail was the detector, and anti-human IgM and IgG were the capture antibodies. The total assay time was <10 min. Sera from 164 individuals classified as either anti-dengue virus IgM positive (94) or anti-dengue virus IgM negative (70) in the reference microplate ELISA with a dengue virus 1 to 4 antigen cocktail were tested in the two commercial assays. The dipstick ELISA missed 7 of 94 positive samples, for a sensitivity of 92.6%, while the immunochromatographic card assay missed two positive samples, for a sensitivity of 97.9%. Of the 70 negative samples, four were false positive by the dipstick ELISA and two were false positive in the immunochromatographic card assay, resulting in specificities of 94.3 and 97.1%, respectively. Both commercial assays provide sensitive and specific detection of anti-dengue virus IgM antibody and could prove useful in settings where the microplate ELISA is impractical.

Treatment of traveler's diarrhea with ciprofloxacin and loperamide.

To determine the efficacy of loperamide given with long- and short-course quinolone therapy for treating traveler's diarrhea, 142 US military personnel were randomized to receive a single 750-mg dose of ciprofloxacin with placebo, 750 mg of ciprofloxacin with loperamide, or a 3-day course of 500 mg of ciprofloxacin twice daily with loperamide. Culture of pretreatment stool specimens revealed campylobacters (41%), salmonellae (18%), enterotoxigenic Escherichia coli (ETEC, 6%), and shigellae (4%). Of the participants, 87% completely recovered within 72 h of entry. Total duration of illness did not differ significantly among the three treatment groups, but patients in the 3-day ciprofloxacin plus loperamide group reported a lower cumulative number of liquid bowel movements at 48 and 72 h after enrollment compared with patients in the single-dose ciprofloxacin plus placebo group (1.8 vs. 3.6, P = .01; 2.0 vs. 3.9, P = .01). While not delivering a remarkable therapeutic advantage, loperamide appears to be safe for treatment of non-ETEC causes of traveler's diarrhea. Two of 54 patients with Campylobacter enteritis had a clinical relapse after treatment that was associated with development of ciprofloxacin resistance.

Vivax malaria resistant to treatment and prophylaxis with chloroquine.

Chloroquine has been the treatment of choice for vivax malaria for more than 40 years. Lately, several case-reports have suggested the emergence of resistance to chloroquine in Plasmodium vivax in Papua New Guinea and Indonesia. We undertook prospective treatment and prophylaxis trials of chloroquine in children and adults with vivax malaria living in Irian Jaya (Indonesia New Guinea). 46 villagers with P vivax parasitaemia were treated with chloroquine by mouth (25 mg base/kg body weight divided over 3 days) and followed up for 14 days. Parasitaemia cleared initially but recurred within 14 days in 10 (22%) subjects. All recurrences were in children younger than 11 years, 7 of whom were younger than 4 years; the failure rate among children under 4 was 70%. 7 of the patients with recurrences were given a second course of chloroquine. In all, the infections initially cleared but recurrent parasitaemia developed in 5 (71%) within 14 days. Whole-blood chloroquine concentrations were consistently above those previously shown to cure P vivax blood infections (90 micrograms/L whole blood). Subjects whose initial infections cleared and who had no parasitaemia on day 14 received weekly prophylaxis with chloroquine. Despite the presence of expected blood chloroquine concentrations, P vivax parasitaemia developed in 9 of 17 subjects receiving prophylaxis during 8 weeks of follow-up (median time to parasitaemia 5.3 weeks). Chloroquine can no longer be relied upon for effective treatment or chemoprophylaxis of P vivax blood infections acquired in this part of New Guinea.