Scale up of anaesthesia services in underserved rural Tanzania.

BACKGROUND: Because of critical shortage of physician anaesthesiologists, the government of Tanzania adopted a task shifting strategy for provision of anaesthesia services. This paper describes the results of an operational study designed to increase the number of anaesthesia providers for emergency obstetric surgeries in order to reduce maternal and perinatal mortality in underserved rural Tanzania. METHODS: In 2016 a before-after cohort study was conducted in seven health centres in rural Tanzania. Five health centres received an intervention and two were selected to track secular trends (control group). Ten associate clinicians, i.e. assistant medical officers, clinical officers, and nurse midwives, from five health centres were trained in anaesthesia skills for emergency obstetric surgeries for three months followed by quarterly supportive supervision, mentoring and teleconsultation to reinforce skills. Primary and secondary outcome measures included Caesarean delivery (CD) rate, quality and safety of anaesthesia, and uptake of the educational program for anaesthesia. RESULTS: Out of the 2,179 CDs performed in the intervention facilities from 2016 to 2019, two women died from complications of anaesthesia. The risk of death from anaesthetic complications was 0.9 per 1000 CD (95% CI 0.1-3.3. The risk of death was not established in the control group because of inadequate documentation and records keeping. The proportion of CD performed under spinal anaesthesia in intervention facilities doubled from 28% (60/214 with 95% CI 22-35) at baseline (July 2014 - June 2016) to 57% (558/971 with 95% CI of 54-61) in year three (July 2018 - June 2019), while in the control group increased by only 40% from 19% (92/475 with 95% CI of 16-23) at baseline and 27% (68/251 with 95% CI of 22-33) in year three. In 2020I, this educational training program was then adopted by the government with minor content changes and increasing duration of training to six months. CONCLUSIONS: This three month educational training program for associate clinicians in anaesthesia, complemented by supportive supervision, can increase the CD rate to one that fills the "unmet need" and the proportion of operations performed under spinal anaesthesia, the gold standard technique for CD. The program can be used to meet the urgent demand for anaesthesia services in other underserved areas in Africa.

Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria.

1. The aim of this study was to assess the pharmacokinetics, clinical efficacy and safety of artemisinin alone and in combination with mefloquine. 2. Thirty-eight adults with symptomatic Plasmodium falciparum malaria were randomly assigned to receive either artemisinin (500 mg single dose followed by another 500 mg on day 1 and then 250 mg twice daily for 4 days) or artemisinin (500 mg single dose followed by 750 mg on day 1 and then 250 mg three times daily for one more day) in co-administration with mefloquine (250 mg three times daily for the first day). All drug administration was by the oral route. Patients were hospitalized at the Kibaha Designated District Hospital, Kibaha, Tanzania, for 6 days and a follow up for 3 weeks was performed. 3. Treatment with the artemisinin/mefloquine combination resulted in a shorter parasite clearance time (PCT) of 24 (22, 27; 95% confidence interval) h vs 31 (27, 36) h and fever subsidence time (FST) of 14 (12, 16) h vs 20 (18, 23) h compared with artemisinin monotherapy. The 95% CI for the difference of the PCT and FST were 1.7, 12 and 3, 10, respectively. Parasites were detected in 7 out of 17 patients (41%) receiving artemisinin monotherapy at the 3rd and 4th week follow up visits. No parasites were detected after the combination therapy. 4. The maximum plasma concentrations (Cmax) were similar after artemisinin monotherapy (615.4 +/- 387.0 ng ml-1) and in combination with mefloquine (851.8 +/- 523.6 ng ml-1). Elimination half-lives (t1/2) were also identical at 2.2 +/- 0.6 h and 2.5 +/- 0.7 h, respectively. However, the AUC values were higher (P < 0.05) after combination therapy (3252 +/- 1873 ng ml-1 h) than after monotherapy (2234 +/- 1502 ng ml-1 h). The oral clearance values were lower (P < 0.05) after combination therapy (195.4 +/- 86.9 l h-1) than after monotherapy (314.3 +/- 189.4 l h-1). PCT and FST normalized to initial parasitaemia correlated with AUC(0, t) (rs = 0.56, P = 0.02, rs = 0.58, P = 0.01, respectively) and with Cmax (rs = 0.62, P = 0.01, rs = 0.68, P = 0.005, respectively) in the artemisinin monotherapy only. 5. One patient on the combination therapy developed a psychiatric condition and two patients on the monotherapy developed skin itch.

Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients.

The study compared the clinical efficacy and safety of oral artemisinin and oral artesunate as well as artemisinin pharmacokinetics during and after resolution of falciparum malaria. Forty adults with symptomatic falciparum malaria were allocated at random to treatment with either oral artemisinin (500 mg single dose on day 1 followed by 250 mg twice daily for 4 d and then another 500 mg single dose on day 6) or with oral artesunate (100 mg single dose on day 1 followed by 50 mg twice daily for 5 d). Patients were admitted to hospital at the Kibaha Designated District Hospital, Kibaha, Tanzania for the duration of treatment. The patients were seen once weekly for 3 more weeks. The time to parasite clearance (PCT) after oral artesunate (26.4 +/- 3.6 h) was shorter (P = 0.002) than after artemisinin (31 +/- 3.6 h). The fever subsidence time (FST) after oral artesunate (18.9 +/- 4.0 h) was also shorter (P = 0.04) than after artemisinin (21.8 +/- 4.6 h). Parasites were detected in 4 (20%) and 7 (35%) patients after completing treatment with artesunate and artemisinin respectively. In these patients the parasitaemia reappeared at the 3rd or 4th week of follow-up. Standard haematology, blood biochemistry and urinalysis, performed before drug intake and again on days 6 and 14, were normal. No clinical abnormality was observed during the study period. Artemisinin plasma concentrations, determined by high performance liquid chromatography with post-column derivatization and detection by ultraviolet light, were followed up to 8 h after drug administration on days 1 and 6. Artemisinin absorption was rapid, the maximum plasma concentrations (Cmax) being attained at about 3 h. Artemisinin areas under the plasma concentration-time curve (AUC) and the Cmax values were about 6 times higher after the first dose on day 1 than on day 6. This decrease in artemisinin plasma concentration is suggestive of an increase in metabolic capacity due to pronounced autoinduction.

Efficacy of oral and intravenous artesunate in male Tanzanian adults with Plasmodium falciparum malaria and in vitro susceptibility to artemisinin, chloroquine, and mefloquine.

The clinical efficacy of oral and intravenous (iv) artesunate was compared in an open randomized trial in 50 male adult patients with uncomplicated Plasmodium falciparum malaria in Kibaha, Tanzania. Oral artesunate treatment was started with 2 x 50 mg initially followed by 50 mg 12 hr later and then 50 mg twice a day for four days (total dose = 550 mg or 9.6 mg/kg). Intravenous artesunate administration began with 2 x 0.8 mg/kg initially followed by 0.8 mg/kg 12 hr later and then 0.8 mg/kg twice a day for four days (total dose = 8.8 mg/kg). The mean +/- SD parasite clearance times (PCTs) were nearly identical at 23.4 +/- 5.9 hr and 24.2 +/- 7.2 hr after oral and iv administration, respectively. Mean +/- SD fever subsidence times (FSTs) were also similar at 18.7 +/- 8.3 hr and 21.0 +/- 4.8 hr, respectively. All patients remained negative for P. falciparum for at least 14 days. Recrudescence/reinfection occurred between days 21 and 28 in five of 25 patients (20%) after oral treatment and in four of 25 patients (16%) after iv treatment. The mean erythrocyte count and hemoglobin concentration were slightly reduced after iv treatment but remained in the normal range. Otherwise, there was no change in blood biochemistry, hematology, and electrocardiograms monitored prior to and during the last dose. It is concluded that treatment with oral and iv artesunate was equally efficacious and well tolerated. A 24-hr in vitro susceptibility test of P. falciparum to artemisinin, chloroquine, and mefloquine was performed in samples from all patients. The three compounds exhibited 100% inhibition with the exception of three isolates, which showed chloroquine resistance. Parameter estimates of a sigmoid Emax model (drug concentration at which 50% of the growth inhibition occurs [EC50]), the sigmoidicity factor s and EC95 fitted to the growth inhibition data differed between compounds and isolates, indicating different sensitivity of P. falciparum isolates. There was no correlation between artemisinin and mefloquine EC50 values, while artemisinin and chloroquine EC50 values showed weak correlation (r2 = 0.223, P = 0.006). There was no correlation between parameters describing clinical outcome (the PCT, the time needed for reduction of the parasite density to 50% and 95% of the initial parasitemia, and the FST) and those describing in vitro susceptibility.