Estimating the annual risk of infection with Mycobacterium tuberculosis among adolescents in Western Kenya in preparation for TB vaccine trials

doi:10.21203/rs.2.9381/v3

Background: Adolescents are a prime target group for tuberculosis (TB) vaccine trials that include prevention of infection (POI). The BCG vaccine is given at birth and does not prevent TB infection. TB infection, a critical endpoint for POI vaccine trials would need to be documented to estimate sample sizes in target populations. Methods: Adolescents aged 12-18 years of age were enrolled in an area under continuous demographic surveillance. A tuberculin skin test (TST) survey was conducted as part of a study on TB prevalence and incidence. All adolescents got TSTs at enrolment and returned after 72 hours for reading. A TST of ≥10mm if HIV negative or ≥ 5mm if HIV positive, was considered positive. Results: Of 4808 adolescents returning for TST readings (96% of those enrolled), mean age was 14.4 (SD 1.9), 4518(94%) were enrolled in school and 21(0.4%) gave a previous history of tuberculosis. Among adolescents with TST reactivity, the mean TST induration was 13.2 mm (SD 5.4). The overall prevalence of latent TB infection was 1544/4808 (32.1%, 95% CI 29.2-35.1) with a corresponding annual risk of TB infection (ARTI) of 2.6% (95% CI 2.2-3.1). Risk factors for a positive TST included being male (OR 1.3, 95%CI 1.2,1.5), history of having a household TB contact (OR 1.5, 95%CI 1.2,1.8), having a BCG scar (OR 1.5,95%CI 1.2,1.8), living in a rural area (OR 1.4, 95%CI 1.1,1.9), and being out of school (OR 1.8, 95%CI 1.4,2.3). Conclusion: We conclude that the high TB transmission rates we found in this study, suggest that adolescents in this region may be an appropriate target group for TB vaccine trials including TB vaccine trials aiming to prevent infection.

Interdisciplinary Medicine

ARTI

tuberculosis

adolescents

TST

risk factors

TB vaccines

Moderate to severe postoperative pain after craniotomy has an incidence as high as 80% (1). Uncontrolled postoperative pain may contribute to increased intracranial pressure (ICP) and hypertension, which may be detrimental, especially for patients with cerebral aneurysms(2).Therefore, postoperative pain control should be a priority for neurosurgical patients.

An increasing number of studies have suggested that multimodal pain treatment, which combines systemic analgesics and local anesthetics, optimizes pain relief and limits adverse effects of opioids (3,4). For example, scalp nerve block and local anesthetic infiltration of the scalp have been proposed to blunt hemodynamic response to craniotomy, decrease opioid consumption, and reduce postoperative pain perception(5-7). Additionally, both scalp blocks and local anesthetic infiltration were recommended for enhanced recovery after surgery (ERAS) for oncological craniotomies, although the current evidence is not sufficient to create a standardized ERAS protocol for oncological craniotomy (8). However, whether scalp nerve block or local anesthetic infiltration is more effective for analgesia has not been evaluated in craniotomy for cerebral aneurysms.

Surgery can initiate the inflammatory stress response. Surgical stress induces the migration of inflammatory cells that release cytokines, primarily interleukin (IL)-6, causing a local inflammatory response at the injured site. Then, when cytokines subsequently release into human plasma, systemic inflammation may occur that leads to an increase in C-reactive protein (CRP) and T- and B-cell activation in bone marrow and blood (9). Later, compensatory anti-inflammatory cytokines, such as IL-10, are produced that cause a reduction in pro-inflammatory cytokine synthesis(10,11). Accordingly, acute-phase proteins, such as CRP, and cytokines, such as IL-6 and IL-10, are thought to be early measures of inflammatory response induced by surgical trauma. Local anesthetics via a nerve block have been demonstrated to attenuate the local inflammatory response(12).For instance, previous animal experiments have demonstrated that C-fiber blockade may inhibit peripheral inflammation in the corresponding innervated zone(12,13). Furthermore, in postoperative patients, peripheral nerve blocks have been shown to attenuate postoperative inflammatory response in knee arthroplasty(14,15). The scalp is densely innervated with C-fibers (unmyelinated) and A-delta fibers (thinly myelinated)(16).

However, as far as we know, no study has attempted to investigate the impact of scalp nerve block on inflammatory response in the craniotomies.

Therefore, the goal of this prospective, randomized, controlled study was to compare the impact of scalp nerve block and local anesthetic infiltration with 0.75% ropivacaine on postoperative inflammatory response, intraoperative hemodynamic response, pain scores, and oxycodone consumption in the first 48 hrs postoperatively in patients undergoing craniotomy for cerebral aneurysms.

Study design and sample size:

The study area, Karemo Division with a population of 85,000 people, part of Siaya County is under a continuous health and demographic surveillance system (HDSS)¹⁰. The HDSS collects biannual data using household surveys. In brief, the study area was divided into 17 clusters of approximately equal population size. The clusters were randomly selected to give each adolescent an equal probability of participation. Eight out of 17 clusters were used for enrolment. In each cluster, HDSS data was used to identify households with adolescents; parents at these households were then approached to have their children participate in the study. The survey was conducted as part of a study on TB prevalence and incidence which used a prospective observational cohort design enrolling adolescents aged 12-18 years¹¹.

Study Procedures

Informed Consent and clinical interviews

Parental consent was obtained at home by study staff prior to inviting adolescents to a mobile field site where minor assent was obtained prior to study participation. During enrolment, standard social demographic data were collected including age, gender, school enrolment status, parental social economic status, parental mortality, recent migration, and urban or rural residence. In addition, several clinical characteristics were collected including history of immunization with BCG, history of tuberculosis, BCG scar (we used the presence of a scar to stratify BCG status), weight and height. Study procedures have been described in more detail elsewhere¹¹. The study received ethical approval of the Kenya Medical Research Institute and the US Centres for Disease Control and Prevention.

Tuberculin skin test and HIV testing:

All enrolled adolescents were offered a tuberculin skin test (TST) for LTBI after they provided a clinical history and vital signs were recorded. The TST used 0.1 ml of tuberculin purified protein derivative (PPD) containing 5TU (tuberculin units) RT23 with Tween 80 (Statens Serum Institute, Copenhagen, Denmark) and was injected intradermally into the middle dorsal region of the right forearm using a disposable tuberculin syringe and G.26 needle. Adolescents were offered a TST after giving clinical history and getting vital signs recorded. Adolescents returned after 72 hours for the reading of their TST results. Late TST readings were allowed up to a maximum of 7 days. All adolescents were offered HIV counselling and testing during the TST reading day. Parental/ guardian consent and adolescent assent were obtained prior to conducting HIV testing. Adolescents identified with HIV were referred to HIV care and treatment services at the Patient Support Centre at the Siaya District Hospital or to the nearest accessible Patient Support Centre.

The TST cut off we used as evidence for LTBI was ≥10mm in adolescents that did not have HIV or whose HIV status was unknown and ≥5mm in adolescents with HIV ¹².

Statistical Analysis

Statistical analysis was performed using SAS 9.2 (SAS Institute Inc., Cary, NC, US). A three point moving average was used on the TST induration data to look for digit preference by observing differences in peaks between actual and smoothed data. The point prevalence of LTBI and 95% confidence intervals were calculated using survey procedures in SAS and adjusted for clustering. The prevalence of LTBI was estimated using the cut-off method and mirror method¹³. The cut-off method used the study defined cut-off of 10mm. In the mirror method, the mode of the distribution of those with presumed tuberculous infection is derived from the overall frequency distribution of TST reactions among the adolescents. Then, the total number of adolescents with positive TST reactions was estimated as the sum of the number of adolescents showing reaction sizes equal to the mode and double the number of adolescents with reaction sizes larger than the mode¹³. Bivariate analysis was used to determine significant associations between various risk factors and a positive tuberculin skin test. Factors significant at the p<0.2 level were further explored in a multivariate model using logistic regression. ARTI was calculated with the formula ARTI=1-(1-prevalence of infection)^{1/mean age14}..

Patient Demographics and Perioperative Characteristics

Fifty-seven patients agreed and were randomized into the study, and 6 patients were excluded from the study after randomization due to unexpected sedation after surgery and delayed extubation (n=5, 1 in Group C, 2 in Group I and 2 in Group S) or reoperation (n=1 in group I). Thus, the remaining 51 patients were analyzed (18 in Group S, 16 in Group I and 17 in Group C). The consort diagram showed the flow of participants through each stage of a randomized trial (Figure 1).

The three groups were similar in age, gender, BMI, ASA, type of aneurysm, duration of operation, duration of anesthesia, cumulative dose of propofol, total loss of blood, urine volume and infusion volume. There were significant differences among the study groups (F=205.377; P<0.001, Table 1) for the cumulative dose of remifentanil. Patients in Group C received a higher cumulative dose of remifentanil (4.59±0.64 mg) compared to Group I (3.67±0.38 mg) and Group S (1.40±0.38 mg) (P<0.001, P<0.001, respectively). Patients in Group I consumed more remifentanil during the operation than patients in Group S (P<0.001).

Additionally, 8 patients (47.1%) in Group C, 3 patients (18.8%) in Group I, and 1 patient (5.6%) in Group S used nicardipine during the operation. Nicardipine administration was different among the three groups (P=0.017 according to Fisher’s exact test, Table 1), and nicardipine was less frequently required in Group S than in group C (P=0.007, Table 1).

Plasma concentrations of CRP, IL-6, and IL-10

Plasma concentrations of CRP, IL-6, and IL-10 at all time points are displayed in Figures 2. Plasma CRP levels significantly changed with time in the three groups (main effect of time: F(3.874, 185.944) = 108.039, P<0.001). In all groups, CRP levels increased 24 hrs after surgery, reaching maximum values at 24 hrs, and subsequently decreased gradually until 72 hrs after the operation (Figure 2A). Additionally, there was no significant interaction between analgesia mode and time in plasma levels of CRP (group-time interaction: F(7.748, 185.944) = 1.43, P =0.069). Although plasma CRP was not significantly different among the three groups, there was a tendency for lower CRP in Group S compared to Groups C and I 12 and 24 hrs postoperatively (Figure 2A).

The same trend applied to IL-6 levels. There was a significant difference over time among the three groups in plasma IL-6 values (main effect of time: F(2.238, 107.447) = 303.761, P <0.001). IL-6 values increased 24 hrs after surgery, reaching peak at 24 hrs and decreasing gradually until 72 hrs after the operation (Figure 2B). Moreover, there was a significant interaction between analgesia mode and time on plasma levels of IL-6 (group-time interaction: F(4.477, 107.447) =2.47, P=0.043), and patients in Group S had lower IL-6 6 hrs postoperatively compared with those in Groups C and I (P=0.001, and P=0.009, respectively) (Figure 2B).

Plasma IL-10 levels significantly changed with time in all three groups (main effect of time: F(3.189, 153.067) = 198.014, P <0.001). In all three groups, IL-10 levels increased 48 hrs after surgery, reaching maximum values at 12 hrs, and subsequently decreased gradually until 72 hrs after the operation (Figure 2C). There was a significant interaction between analgesia mode and time on plasma levels of IL-10 (group-time interaction: F(6.378, 153.067) = 5.107, P<0.01). Furthermore, patients in Group S had higher IL-10 levels 12 and 24 hrs postoperatively compared with those in Groups C and I (12 hrs: P=0.012, and P<0.001, 24 hrs: P=0.011, and P<0.001, respectively) (Figure 2C).

Hemodynamic parameters (HRs and MAPs)

HRs were significantly lower in Groups I and S compared to Group C at T3, T4, T5 and T6 (group-time interaction: F(3.46, 166.075) =86.081, P<0.001). Post hoc analysis showed significant differences during skin incision (T3) (P=0.03, P=0.035, respectively) and the second (T4) (P<0.001, P<0.001, respectively) and fifth minutes (T5) after incision (P<0.001, P<0.001, respectively) and during dura opening (T6) (P =0.032, P<0.001, respectively). There were no significant differences in HRs between Group S and Group I at any time point (P>0.05) (Figure 3A).

There were significant differences in MAP among the three groups at T3, T4, T5 and T6 (group-time interaction: F(6.995, 167.883) = 24.192, P<0.001). Post hoc analysis showed that MAPs were significantly lower in Group I and Group S compared to Group C during skin incision (T3) (Group S vs. Group C: P<0.001, Group I vs. Group C: P<0.001). Additionally, MAPs in Group S were significantly lower than those in Group I and Group C at the second (T4) and fifth minutes (T5) after the incision and during dura opening (T6) (T4, T5 and T6: Group S vs. Group I, P<0.001; Group S vs. Group C, P<0.001). However, there were no significant differences in MAPs between Groups I and C at T4, T5 and T6 (P>0.05) (Figure 3B).

Postoperative pain scores and oxycodone consumption

The VAS scores were significantly lower in Group S than in Group C and Group I 2, 4, 8, 12, 24 and 48 hrs postoperatively (P<0.001, respectively). However, Group I only had lower VAS scores compared to Group C 2 hrs after surgery (P=0.026) (Figure 4).

The time intervals from patient recovery to the first use of oxycodone in Groups I and S were significantly longer than those in Group C [5.75(3.58-9.28) and 9.85 (7.93-14.83) vs. 1.5(0.8-3.65) hrs, P=0.009, and P<0.001, respectively]. In addition, the first use of oxycodone in Group S was significantly longer than that in Group I (P=0.018) (Figure 5A).

Oxycodone consumption after 48 hrs was significantly higher in Groups C and I than in Group S (27±9.6 and 22.06±12.24 vs. 5.01±4.3 mg, P<0.001, P<0.001, respectively). There was no significant difference in oxycodone consumption between Groups I and C (P=0.386) (Figure 5B).

Pain control-related adverse events during the study period

Adverse events 48 hrs after surgery, such as respiration depression, cutaneous pruritus, subcutaneous hematomas, scalp infection, and local anesthetic toxicity were not observed. However, the incidence of PONV was significantly different among the three groups (P=0.017, Table 2.). Five patients (29.4%) in Group C, 4 patients (25%) in Group I and 2 patients (11.1%) in Group S suffered from PONV, and PONV occurred less frequently in Group S than Group C (P=0.012, Table 2). There were no significantly differences in the incidence of fever or dizziness among groups (P=0.721, P=0.462, respectively, Table 2).

This prospective, randomized, controlled study demonstrated that scalp nerve block with 0.75% ropivacaine had a modest preventive effect on postoperative inflammation demonstrated by lower IL-6 concentrations in plasma 6 hrs after craniotomy for cerebral aneurysms and reduced CRP levels and increased IL-10 levels 12 and 24 hrs postoperatively. Scalp nerve block blunted the hemodynamic response to skin incision better than local anesthetic infiltration or routine anesthesia. Additionally, both the scalp nerve block and local anesthetic infiltration decreased remifentanil consumption during the operation compared to the control group, and the scalp nerve block group had lower postoperative pain intensity, longer duration before the first dose of oxycodone, less consumption of oxycodone and lower incidence of PONV 48 hours postoperatively than the local anesthetic infiltration group and the control group.

Substances released by sensory nerve endings produce inflammation in the target tissue, which is a progress of neurogenic inflammation response (18). The key point of neurogenic inflammation is the activation of the primary afferent，which cause dorsal root reflexes in the spinal cord (19). Blocking the nerve through local anesthetics can reduce the release of substances, such as substance P and calcitonin gene–related peptide, and block neural transmission at the site of tissue injury, thereby alleviating the neurogenic inflammatory response(20). However, the exact mechanisms are still largely unclear.

Therefore, it is possible that in the current study, the reduced concentrations of pro-inflammatory cytokines CRP and IL-6, as well as the increased concentration of anti-inflammatory cytokine IL-10 in plasma, compared to local anesthetic infiltration and routine analgesia, were related to the local anti-inflammatory effects of scalp nerve block. It is possible that scalp nerve block has a greater deafferentation effect than local anesthetic infiltration that prevents the development of peripheral and systemic inflammation. There is also evidence suggesting that inflammation and pain are related(21). In the current study, patients in the scalp nerve block group had lower postoperative pain intensity and longer duration before the first dose of oxycodone than patients in the local anesthetic infiltration and routine analgesia groups, supporting our findings that scalp nerve block inhibited craniotomy-induced inflammation.

The effects of neuraxial blockade with local anesthetics on postoperative inflammatory response are still controversial. For example, a previous study suggested that a combined continuous lumbar plexus and sciatic nerve blocks with 0.2% ropivacaine contributed to the attenuation of postoperative inflammatory response, which was demonstrated by decreased CRP and IL-6 concentrations in plasma 24 and 48 hrs postoperatively (14). Another clinical study using more extensive nerve blocks, such as epidural analgesia, have also indicated attenuated ex vivo pro-inflammatory cytokine IL-6 and anti-inflammatory cytokine IL-10 production after visceral surgery(22). However, Moore and coworkers found that the circulating CRP and IL-6 response to pelvic surgery was unaffected by extradural analgesia(23). This finding is in contrast with the present study where the scalp nerve block inhibited CRP and IL-6. Such discrepancies could originate from the nerve block technique, the type of surgery, and probably the assay used to measure the inflammatory mediator concentration (i.e., ex vivo or in vivo assays).

Of note is that, in our study, scalp nerve block only had modest anti- inflammatory effects. Previous studies have indicated the impacts of remifentanil on systemic inflammation. For example, remifentanil has been indicated to reduce plasma IL-6 levels on the seventh day after abdominal surgery(24). It has also been demonstrated to inhibit exaggerated inflammation after cardiac surgery with cardiopulmonary bypass(25). In the present study, we found that patients in the scalp nerve block group consumed less remifentanil during the operation than patients in the local anesthetic infiltration group and the routine analgesia group. Therefore, remifentanil requirements may be a confounding factor that hampered the interpretation of the effects of different analgesic modalities on the inflammatory response caused by craniotomy. Furthermore, our study might have been underpowered because of the small study group size, which could also explain the modest anti-inflammatory effects of scalp nerve block. Collectively, our findings suggest a potential anti-inflammatory effect of scalp nerve block with 0.75% ropivacaine, pending further investigations.

Acute increases in MAP and HR could be deleterious for neurosurgical patients with cerebral aneurysm, given that acute arterial hypertension and tachycardia may result in ruptured cerebral aneurysms. In the current study, we found that scalp nerve block blunted hemodynamic response to skin incision and dura opening better than local anesthetic infiltration or routine anesthesia. These results are in line with the study by Geze1 et al (7), in which scalp nerve block with 0.5% bupivacaine was shown to be better at blunting the hemodynamic response to strong nociceptive stimulus, such as head pinning, than local infiltration or routine analgesia(7). However, the it has also been reported that local infiltration promotes intraoperative hemodynamic stability in patients undergoing craniotomy (26-28). Our study is inconsistent with these studies. The discrepancy may be explained by different local anesthetic used (bupivacaine vs. ropivacaine), the time point studies or the nociceptive stimulus.

Both scalp nerve block and local infiltration have been demonstrated to reduce VAS scores and opioid requirements after surgery. For example, a meta-analysis of scalp blocks demonstrated not only a significant reduction in VAS scores 2, 4, 6 and 8 hrs after the operation, with the most significant mean reduction occurring 1 hr after surgery, but also a decrease in opioid requirements over the first 24 hrs postoperatively. However, few studies have compared the effects of scalp nerve block and local infiltration on postoperative pain control. In the current study, we found that the scalp nerve block group had lower postoperative pain intensity, longer duration of time before the first dose of oxycodone, less consumption of oxycodone and lower incidence of PONV 48 hrs postoperatively than the local infiltration group and control group. Our study is consistent with the study by Hwang et al (29), showing that scalp blocks with 0.75% levobupivacaine effectively lowered postoperative pain and PCA consumption 72 hrs after patients underwent frontoparietal craniotomy for aneurysm clipping compared to routine analgesia. In our study, the beneficial effect of the scalp block lasted longer than the expected duration of action. This phenomenon could be explained by preemptive analgesia(30), which commences before surgery and continues in the postoperative period, preventing the establishment of peripheral and central sensitization since we performed the scalp block prior to scalp incision(31).

It is noteworthy that in our study, PONV occurred less frequently in the scalp nerve block group than the local infiltration group and the control group. It is possible that the lower incidence of PONV in the scalp nerve block group was related to less intraoperative remifentanil consumption and postoperative oxycodone use.

The current study has several limitations. First, 0.75% ropivacaine (15 mL, 112.5 mg) was used for the scalp nerve block and local infiltration, but the plasma concentration was not measured, and the maximum recommended dose of ropivacaine is 225 mg with or without epinephrine(32). Furthermore, in our study, no patient developed side effects related to local anesthetic toxicity. Second, we did not apply isotonic sodium chloride for the scalp nerve block or local infiltration in the control group. Thus, we could not rule out the effects of injection stress. Third, in the present study, we only focused on the effects of different analgesic modalities on systemic inflammatory response but not local inflammatory response at the site of tissue injury. Fourth, because the impact of different analgesic modalities on inflammatory response to craniotomy has been rarely reported, in the current pilot study, the sample size calculation was done based on MAP and not inflammatory markers in response to craniotomy. Accordingly, the present study may not be sufficiently powered to provide strong evidence for the effects of scalp nerve block and local anesthetic infiltration on inflammatory response, hemodynamic response, or postoperative pain control in patients undergoing craniotomy due to the small sample size. A larger study with adequate power is needed to validate our results. Finally, in the current study, we only evaluated the effect of the ropivacaine scalp block on acute pain after craniotomy (48 hrs postoperatively) but not chronic postcraniotomy headache. These limitations indicate the need for further investigations.

In conclusion, the present study shows that scalp nerve block with 0.75% ropivacaine attenuated inflammatory response to craniotomy for cerebral aneurysms, blunted hemodynamic response to scalp incision, and controlled postoperative pain better than local anesthetic infiltration or routine anesthesia. Scalp nerve block should be considered in conjunction with general anesthesia for aneurysm clipping. Scalp nerve block might exert potential anti-inflammatory neuroanesthetic effects pending further investigations.

SNB: scalp nerve block LA: local anesthetic infiltration

ICP: increased intracranial pressure ERAS: enhanced recovery after surgery

IL-6: interleukin-6 CRP: C-reactive protein VAS: visual analog scale GCS:Glasgow coma score PONV: postoperative nausea and vomiting

ETCO2: end-tidal CO2 BIS: bispectral index SQI: signal quality index

EMG: electromyography MAP: mean arterial pressure

paCO2: partial pressure of carbon dioxide in the artery HR: heart rate

PACU: post-anesthetic care unit NICU: neurosurgical intensive care unit

IQR: interquartile range

Ethics approval and consent to participate

This study was approved by the research ethics committee of Zhongnan Hospital of Wuhan University (No.2016013), and written informed consent was obtained from all subjects participating in the trial.

(2) Consent for publication:

Not Applicable

(3) Availability of data and materials

The datasets generated and analyzed in the current study are available from the corresponding author on reasonable request.

(4) Competing interests:

The authors declare no conflict of interest.

(5) Funding

This research was supported by the National Natural Science Foundation of China (no. 81371195 and no. 81870851), a research grant from the Outstanding Talented Young Doctor Program of Wuhan (2014), and the Technology and Innovation Seed Fund (no. cxpy2017038) of Zhongnan Hospital of Wuhan University. The funding bodies played the roles in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

(6) Authors' contributions

Each author's individual contributions to the manuscript are as follows:

1. XY: This author helped enroll patients in the study and test patient samples.

2. JM: This author helped record experimental data and gather specimens.

3. RD: This author helped group the patients.

4. YYL, LC and KL: These authors helped analyze the data.

5. MP and ZZZ: These authors helped design experiments and write the manuscript.

(7) Acknowledgments:

Not applicable.

1. Flexman AM, Ng JL, Gelb AW. Acute and chronic pain following craniotomy. Curr Opin Anaesthesiol 2010;23:551-7.

2. Owens WB. Blood pressure control in acute cerebrovascular disease. J Clin Hypertens (Greenwich) 2011;13:205-11.

3. Lee EJ, Lee MY, Shyr MH, Cheng JT, Toung TJ, Mirski MA, Chen TY. Adjuvant bupivacaine scalp block facilitates stabilization of hemodynamics in patients undergoing craniotomy with general anesthesia: a preliminary report. J Clin Anesth 2006;18:490-4.

4. Guilfoyle MR, Helmy A, Duane D, Hutchinson PJ. Regional scalp block for postcraniotomy analgesia: a systematic review and meta-analysis. Anesth Analg 2013;116:1093-102.

5. Batoz H, Verdonck O, Pellerin C, Roux G, Maurette P. The analgesic properties of scalp infiltrations with ropivacaine after intracranial tumoral resection. Anesth Analg 2009;109:240-4.

6. Law-Koune JD, Szekely B, Fermanian C, Peuch C, Liu N, Fischler M. Scalp infiltration with bupivacaine plus epinephrine or plain ropivacaine reduces postoperative pain after supratentorial craniotomy. J Neurosurg Anesthesiol 2005;17:139-43.

7. Geze S, Yilmaz AA, Tuzuner F. The effect of scalp block and local infiltration on the haemodynamic and stress response to skull-pin placement for craniotomy. Eur J Anaesthesiol 2009;26:298-303.

8. Hagan KB, Bhavsar S, Raza SM, Arnold B, Arunkumar R, Dang A, Gottumukkala V, Popat K, Pratt G, Rahlfs T, Cata JP. Enhanced recovery after surgery for oncological craniotomies. J Clin Neurosci 2016;24:10-6.

9. Kishimoto T. The biology of interleukin-6. Blood 1989;74:1-10.

10. Hildebrand F, Pape HC, Krettek C. [The importance of cytokines in the posttraumatic inflammatory reaction]. Unfallchirurg 2005;108:793-4, 6-803.

11. Mannick JA, Rodrick ML, Lederer JA. The immunologic response to injury. J Am Coll Surg 2001;193:237-44.

12. Beloeil H, Ababneh Z, Chung R, Zurakowski D, Mulkern RV, Berde CB. Effects of bupivacaine and tetrodotoxin on carrageenan-induced hind paw inflammation in rats (Part 1): hyperalgesia, edema, and systemic cytokines. Anesthesiology 2006;105:128-38.

13. Gentili ME, Mazoit JX, Samii KK, Fletcher D. The effect of a sciatic nerve block on the development of inflammation in carrageenan injected rats. Anesth Analg 1999;89:979-84.

14. Bagry H, de la Cuadra Fontaine JC, Asenjo JF, Bracco D, Carli F. Effect of a continuous peripheral nerve block on the inflammatory response in knee arthroplasty. Reg Anesth Pain Med 2008;33:17-23.

15. Martin F, Martinez V, Mazoit JX, Bouhassira D, Cherif K, Gentili ME, Piriou P, Chauvin M, Fletcher D. Antiinflammatory effect of peripheral nerve blocks after knee surgery: clinical and biologic evaluation. Anesthesiology 2008;109:484-90.

16. Bin Saif GA, Ericson ME, Yosipovitch G. The itchy scalp--scratching for an explanation. Exp Dermatol 2011;20:959-68.

17. Pinosky ML, Fishman RL, Reeves ST, Harvey SC, Patel S, Palesch Y, Dorman BH. The effect of bupivacaine skull block on the hemodynamic response to craniotomy. Anesth Analg 1996;83:1256-61.

18. Szolcsanyi J. Capsaicin-sensitive sensory nerve terminals with local and systemic efferent functions: facts and scopes of an unorthodox neuroregulatory mechanism. Prog Brain Res 1996;113:343-59.

19. Willis WD, Jr. Dorsal root potentials and dorsal root reflexes: a double-edged sword. Exp Brain Res 1999;124:395-421.

20. Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 1993;52:259-85.

21. Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin 2007;45:27-37.

22. Beilin B, Bessler H, Mayburd E, Smirnov G, Dekel A, Yardeni I, Shavit Y. Effects of preemptive analgesia on pain and cytokine production in the postoperative period. Anesthesiology 2003;98:151-5.

23. Moore CM, Desborough JP, Powell H, Burrin JM, Hall GM. Effects of extradural anaesthesia on interleukin-6 and acute phase response to surgery. Br J Anaesth 1994;72:272-9.

24. De Cosmo G, Sessa F, Fiorini F, Congedo E. Effect of remifentanil and fentanyl on postoperative cognitive function and cytokines level in elderly patients undergoing major abdominal surgery. J Clin Anesth 2016;35:40-6.

25. von Dossow V, Luetz A, Haas A, Sawitzki B, Wernecke KD, Volk HD, Spies CD. Effects of remifentanil and fentanyl on the cell-mediated immune response in patients undergoing elective coronary artery bypass graft surgery. J Int Med Res 2008;36:1235-47.

26. Bloomfield EL, Schubert A, Secic M, Barnett G, Shutway F, Ebrahim ZY. The influence of scalp infiltration with bupivacaine on hemodynamics and postoperative pain in adult patients undergoing craniotomy. Anesth Analg 1998;87:579-82.

27. Mohammadi SS, Shahbazian E, Shoeibi G, Almassi F. Effect of scalp infiltration with Bupivacaine on early hemodynamic responses during craniotomy under general anesthesia. Pak J Biol Sci 2009;12:603-6.

28. Hartley EJ, Bissonnette B, St-Louis P, Rybczynski J, McLeod ME. Scalp infiltration with bupivacaine in pediatric brain surgery. Anesth Analg 1991;73:29-32.

29. Hwang JY, Bang JS, Oh CW, Joo JD, Park SJ, Do SH, Yoo YJ, Ryu JH. Effect of scalp blocks with levobupivacaine on recovery profiles after craniotomy for aneurysm clipping: a randomized, double-blind, and controlled study. World Neurosurg 2015;83:108-13.

30. Kaye AD, Baluch A, Kaye AJ, Gebhard R, Lubarsky D. Pharmacology of cyclooxygenase-2 inhibitors and preemptive analgesia in acute pain management. Curr Opin Anaesthesiol 2008;21:439-45.

31. Kissin I. Preemptive analgesia. Anesthesiology 2000;93:1138-43.

32. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med 2004;29:564-75; discussion 24.

Table 1: Demographic characteristics of 4808 adolescents undergoing tuberculin skin testing in Kenya, 2008-2009.

Characteristic	Category	All (4808)
Tuberculin skin test (TST)	Reactive	1544 (32.1%)
	Non reactive	3264 (67.9%)
Gender	Female	2327 (48.4%)
	Male	2481 (51.6%)
School going	Yes	4518 (94.0%)
	No	290 (6.0%)
HIV status	Positive	23 (0.5%)
	Negative	1985 (41.3%)
	Unknown	2165 (45.0%)
Residence	Rural	4550 (94.6%)
	Urban	258 (5.4%%)
Previous TB	Yes	21 (0.4%)
	No	4787 (99.6%)
History of TB contact	Yes	138 (2.9%)
	No	4670 (97.1%)
Deceased parents	One parent deceased or both alive	3519 (73.2%)
	Both deceased	1289 (26.8%)
Socio economic status	Upper class	1582 (32.9%)
	Middle class	1636 (34.0%)
	Lower class	1590 (33.1%)

Table 2: ARTI estimates and prevalence of infection presented for all adolescents, those with and without a BCG scar

	N	Mean age (years)	≥10mm			*Mirror method 17 mm
			P	ARTI	CI (95%)	P	ARTIπ	CI (95%)
All	4808	14.4	32.1%	2.6%	(2.2,3.1)	27.6%	2.2%	(1.8,2.6)
BCG scar	3947	14.4	33.5%	2.7%	(2.2,3.2)	27.8%	2.2%	(1.7,2.7)
BCG scar absent	859	14.2	25.6%	2.1%	(1.1,3.1)	27.0%	2.1 %	(1.1,3.1)

*The total number of adolescents with true reactions was calculated by adding the number of adolescents showing reaction sizes equal to the mode to double the number with reaction sizes larger than the mode to determine the numerator

The Cut-off for HIV+ was ≥5mm

π ARTI formula =1-(1-prevalence of infection) 1/mean age

CI 95% Confidence interval

Table 3: Risk factors for a positive tuberculin skin test (TST) for the 10mm cut-off method and the 17mm mirror method

Risk Factor		Tuberculin skin test >=10mm n=4808			Multivariate	Tuberculin skin test >=17mm n=4808			Multivariate
		Negative	Positive	OR, 95% CI	OR, 95% CI	Negative	Positive	OR, 95% CI	OR, 95% CI
Gender	Female	1650	677/2327 (29.1%)	1		2076	251/2327 (10.8%)	1
	Male	1614	867/2481 (34.9%)	1.3(1.2,1.5)	1.3 (1.2,1.5)	2129	352/2481 (14.2%)	1.4 (1.2,1.6)	1.4 (1.2,1.7)
History of a house hold TB contact	Yes	224	150/374 (40.1%)	1.5 (1.2,1.8)	1.5(1.2,1.8)	119	19/138 (13.8%)	1
	No	3040	1394/4434 (31.4%)	1		4086	584/4670 (12.5%)	1.6 (1.2,2.1)	1.6(1.2,2.1)
Previous TB	Yes	15	6/21 (28.6%)	1		18	3/21 (14.3%)	1
	No	3232	1528/4787 (32.1%)	0.8 (0.3,2.1)		4163	597/4760 (12.5%)	1.2 (0.4,3.7)
BCG Scar	Yes	2623	1324/3947 (33.5%)	1.3 (1.2,1.7)	1.5 (1.3,1.8)	3450	497/3947 (12.6%)	1.0 (0.8,1.3)	1.0 (0.8,1.3)
	No	641	220/861 (25.6%)	1		753	106/859 (12.3%)	1
Residence	Urban	189	69/258 (26.7%)	1		231	27/258 (10.5%)	1
	Rural	3075	1475/4550 (32.4%)	1.2 (1.0,1.5)	1.4 (1.1,1.9)	3974	576/4550 (12.7%)	1.2 (0.8,1.9)	1.2(0.8,1.9)
School going	Yes	3103	1415/4518 (31.3%)	1		3960	558/4518 (12.4%)	1
	No	161	129/290 (44.5%)	1.8(1.4,2.2)	1.8 (1.4,2.3)	245	45/290 (15.5%)	1.3 (0.9,1.8)	1.3(1.0,1.8)
Orphaned	Yes	1136	585/1721 (34.0%)	1		1474	247/1721 (14.4%)	1
	No	2128	959/3087 (31.1%)	1.1 (1.0,1.3)	1.1(1.0,1.3)	2731	356/3087 (11.5%)	1.3 (1.1,1.5)	1.3(1.1,1.5)

supplement1.csv

Estimating the annual risk of infection with Mycobacterium tuberculosis among adolescents in Western Kenya in preparation for TB vaccine trials

Status:

Journal Publication

Version 3

Abstract

Figures

Background

Methods