Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis David R. Boulware, M.D., M.P.H., David B. Meya, M.Med., Conrad Muzoora, M.Med., Melissa A. Rolfes, Ph.D., Katherine Huppler Hullsiek, Ph.D., Abdu Musubire, M.Med., Kabanda Taseera, M.Med., Henry W.

Nabeta, M.B., Ch.B., Charlotte Schutz, M.B., Ch.B., M.P.H., Darlisha A. Williams, M.P.H., Radha Rajasingham, M.D., Joshua Rhein, M.D., Friedrich Thienemann, M.D., Ph.D., Melanie W. Lo, M.D., Kirsten Nielsen, Ph.D., Tracy L. Bergemann, Ph.D., Andrew Kambugu, M.Med., Yukari C. Manabe, M.D., Edward N.

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Janoff, M.D., Paul R. Bohjanen, M.D., Ph.D., and Graeme Meintjes, M.B., Ch.B., Ph.D., for the COAT Trial Team N Engl J Med 2014; 370:2487-2498 DOI: 10.1056/NEJMoa1312884. Methods We assessed survival at 26 weeks among 177 human immunodeficiency virus–infected adults in Uganda and South Africa who had cryptococcal meningitis and had not previously received ART. We randomly assigned study participants to undergo either earlier ART initiation (1 to 2 weeks after diagnosis) or deferred ART initiation (5 weeks after diagnosis). Participants received amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) and fluconazole (800 mg per day) for 14 days, followed by consolidation therapy with fluconazole. Results The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P=0.03).

The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P=0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (.

Figure 1 Screening and Randomization. Of 237 patients with cryptococcal meningitis, 177 were enrolled in the study after 7 to 11 days of antifungal treatment.

One participant randomly assigned to receive earlier antiretroviral therapy (ART) withdrew consent 2 days after randomization. All other participants were followed for 46 weeks or until death. No participants were lost to follow-up. Analyses were performed according to the intention-to-treat principle. Randomization was stratified according to site and the presence or absence of altered mental status (Glasgow Coma Scale [GCS] score.

Figure 2 Cumulative Probability of Survival According to Timing of ART. Overall survival from randomization (time 0) at 7 to 11 days after diagnosis of cryptococcal meningitis to 46 weeks is shown in Panel A. Earlier ART initiation, at 7 to 13 days after diagnosis, was associated with a risk of death within 26 weeks that was 15 percentage points higher than that associated with ART initiation at 5 weeks after diagnosis (P=0.03). Panels B and C show survival stratified according to the cerebrospinal fluid (CSF) white-cell count at the time of randomization. Among study participants with a paucity of CSF white cells (. C ryptococcus neoformans is the most common cause of meningitis in adults in sub-Saharan Africa, and meningitis caused by C. Neoformans accounts for approximately 20 to 25% of deaths from the acquired immunodeficiency syndrome (AIDS) in Africa.

Determining when antiretroviral therapy (ART) should be initiated after a diagnosis of cryptococcal meningitis involves balancing the survival benefit conferred by ART against the risk of the immune reconstitution inflammatory syndrome (IRIS), a paradoxical reaction that occurs during immunologic recovery with ART despite effective therapy for the opportunistic infection. Since 2009, the international standard of care has shifted toward earlier ART initiation after diagnosis of an opportunistic infection; most of the evidence in support of this strategy is for tuberculosis, particularly in persons with CD4 cell counts lower than 50 per cubic millimeter. Conflicting data regarding the relationship between the timing of ART for cryptococcosis and the outcome pose a therapeutic dilemma.

Three randomized trials have differed with respect to both the timing of ART initiation and the results. The AIDS Clinical Trials Group A5164 trial, involving 41 U.S.

And South African participants with cryptococcosis who were receiving amphotericin-based treatment, showed nonsignificant decreases in the rates of death and AIDS progression among those who were randomly assigned to earlier ART initiation (28 days after diagnosis; median, 45 days). In contrast, in a group of 54 patients in Zimbabwe treated with fluconazole monotherapy (800 mg per day), mortality was higher among those randomly assigned to immediate ART (median. Study Population and Setting We enrolled patients at Mulago Hospital, Kampala, and Mbarara Hospital, Mbarara — both in Uganda — and at GF Jooste Hospital in Cape Town, South Africa, beginning in November 2010, February 2011, and April 2011, respectively. Patients with suspected meningitis were screened at the time of hospital presentation and counseled regarding cryptococcosis, HIV and AIDS, ART, and possible research participation. Eligibility criteria for enrollment were an age of 18 years or older, a diagnosis of human immunodeficiency virus (HIV) infection, no previous receipt of ART, a diagnosis of cryptococcal meningitis based on cerebrospinal fluid (CSF) culture or CSF cryptococcal antigen assay, and treatment with amphotericin-based therapy. Exclusion criteria were an inability to undergo follow-up, contraindication for or refusal to undergo lumbar punctures, multiple concurrent CNS infections, previous cryptococcosis, receipt of chemotherapy or immunosuppressive agents, pregnancy, breast-feeding, and serious coexisting conditions that precluded random assignment to earlier or deferred ART.

Women included in the study agreed to use two forms of contraception, because high-dose fluconazole is potentially teratogenic during the first trimester of pregnancy. Written informed consent was obtained from each participant or his or her surrogate. The institutional review board at each participating site approved the study. Study Treatment Patients entered the trial after 7 to 11 days of antifungal treatment. Participants were randomly assigned to receive either ART initiated within 48 hours after randomization (earlier-ART group) or ART initiated 4 weeks after randomization (deferred-ART group). Cryptococcal induction therapy consisted of 2 weeks of treatment with amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) combined with fluconazole (800 mg per day), a regimen that is consistent with international guidelines. Flucytosine, although it is the most effective drug to combine with amphotericin, is unavailable in low-income and middle-income countries.

Enhanced consolidation therapy consisted of 800 mg of fluconazole per day for at least 3 weeks or until a CSF culture was sterile, followed by 400 mg of fluconazole per day thereafter, for a total consolidation period of at least 12 weeks. Secondary prophylaxis with fluconazole (200 mg per day) was then continued for at least 1 year. ART regimens, which were selected before randomization, consisted of either zidovudine or stavudine, each with lamivudine and efavirenz. Tenofovir was avoided as an initial ART medication because of concern about potential nephrotoxicity with concomitant amphotericin treatment. The President's Emergency Plan for AIDS Relief (PEPFAR) provided support for HIV care but not for research.

ART was provided by PEPFAR in Uganda and by the Department of Health in South Africa. Merck Sharp & Dohme donated a reserve supply of efavirenz but did not have any other involvement in any aspect of the trial. Randomization and Follow-up We used a computer-generated, permuted-block randomization algorithm with blocks of different sizes in a 1:1 ratio, stratified according to site and the presence or absence of altered mental status at the time that informed consent was obtained (Glasgow Coma Scale score ≤14 vs.

15; scores can range from 3 to 15, with lower scores indicating reduced levels of consciousness). Sequentially numbered, opaque, sealed envelopes stored in a lockbox contained the randomization assignments for enrolled participants. Envelopes were opened after written informed consent had been obtained. After the initial diagnostic lumbar puncture, therapeutic lumbar punctures were performed, with the use of manometers, on day 7 and day 14 of amphotericin therapy and additionally as needed for the control of intracranial pressure (a median of three lumbar punctures).

Routine care included the administration of intravenous fluids (≥2 liters per day), electrolyte management, and trimethoprim–sulfamethoxazole prophylaxis. Participants were followed daily while hospitalized, then every 2 weeks for 12 weeks and monthly thereafter through 46 weeks.

For details of study conduct, see the and statistical analysis plan, available with the full text of this article at NEJM.org. Study End Points The primary end point was survival at 26 weeks. (The results of the primary analysis are expressed in the text as mortality at 26 weeks.) The secondary end points were survival through 46 weeks, cryptococcal IRIS, relapse of cryptococcal meningitis, fungal clearance, virologic suppression (. Interim Monitoring The National Institute of Allergy and Infectious Diseases data and safety monitoring board for African studies reviewed interim analyses annually. A Lan–DeMets spending-function analogue of the O'Brien–Fleming boundaries was proposed to control the type I error resulting from multiple interim analyses.

After the second review in April 2012, the data and safety monitoring board recommended stopping enrollment because of substantial excess mortality with earlier ART. Enrollment was stopped on April 27, 2012, with 177 participants enrolled. Statistical Analysis We compared the primary end point (survival at 26 weeks) in the treatment groups using time-to-event methods with Cox proportional-hazards models. The study was statistically powered to detect a 25% relative survival benefit (absolute benefit, 15 percentage points) with 90% power and an overall two-sided alpha level of 0.05 with an intended sample size of 500 participants. The a priori assumption was that the survival rate at 26 weeks would be 40 to 50% with the deferred-ART strategy. Survival at 26 weeks was compared among prespecified subgroups defined according to baseline characteristics, with the use of models including an interaction term between treatment group and subgroup. Categorical secondary end points were compared with the use of Fisher's exact test.

To account for the competing risk of death, the cumulative incidence function was used to compare the end points of IRIS, relapse, and adverse events between treatment groups. A linear mixed-effects regression model fit with a random intercept and slope was used to estimate the rate of fungal clearance, measured as the log 10 decrease in colony-forming units (CFU) of cryptococcus per milliliter of CSF per day among all participants for whom two or more cultures were available. All analyses were conducted with SAS software version 9.3 (SAS Institute), according to the intention-to-treat principle, on the basis of a two-sided type I error with an alpha level of 0.05. Participants Among the 389 patients with suspected meningitis who were screened, 177 with cryptococcal meningitis were randomly assigned to a treatment group after a median of 8 days of amphotericin therapy (interquartile range, 7 to 8) ( Figure 1 Screening and Randomization. Of 237 patients with cryptococcal meningitis, 177 were enrolled in the study after 7 to 11 days of antifungal treatment. One participant randomly assigned to receive earlier antiretroviral therapy (ART) withdrew consent 2 days after randomization.

All other participants were followed for 46 weeks or until death. No participants were lost to follow-up. Analyses were performed according to the intention-to-treat principle. Randomization was stratified according to site and the presence or absence of altered mental status (Glasgow Coma Scale [GCS] score. Primary End Point The proportion of participants who died by 26 weeks was greater in the earlier-ART group than in the deferred-ART group (40 of 88 [45%] vs. 27 of 89 [30%]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P=0.03) ( Figure 2 Cumulative Probability of Survival According to Timing of ART.

Overall survival from randomization (time 0) at 7 to 11 days after diagnosis of cryptococcal meningitis to 46 weeks is shown in Panel A. Earlier ART initiation, at 7 to 13 days after diagnosis, was associated with a risk of death within 26 weeks that was 15 percentage points higher than that associated with ART initiation at 5 weeks after diagnosis (P=0.03). Panels B and C show survival stratified according to the cerebrospinal fluid (CSF) white-cell count at the time of randomization. Among study participants with a paucity of CSF white cells (. Subgroup Analyses We assessed prespecified subgroups to determine whether differences in survival between treatment groups at 26 weeks were dependent on participants' baseline clinical characteristics ( Figure 3 Subgroup Analyses of Mortality. Prespecified subgroups were assessed to determine whether differences in survival between treatment groups at 26 weeks were dependent on baseline clinical characteristics. Values for subgroups are 6-month mortality.

The CSF white-cell count at randomization was the only characteristic with a significant interaction, which suggested a differential response to the timing of ART initiation. The only characteristic with a significant interaction was the white-cell count in CSF at randomization (P=0.02 for interaction) (, and ). For the subgroup with a CSF white-cell count of less than 5 cells per cubic millimeter, mortality was higher with earlier ART than with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P=0.008). In contrast, the survival rate was similar between treatment groups in the subgroup with CSF white-cell counts of 5 cells per cubic millimeter or higher at randomization (hazard ratio, 0.88; 95% CI, 0.46 to 1.71; P=0.71). Earlier ART was not favorable in any subgroup analyzed, including participants at high risk for death, such as those with CD4 cell counts of less than 50 per cubic millimeter (hazard ratio, 1.74; 95% CI, 0.93 to 3.24) and those with an altered mental status (Glasgow Coma Scale score.

Secondary End Points The timing of ART initiation did not influence any of the secondary end points ( Table 2 Secondary Outcomes in the Two Treatment Groups. Even the cumulative incidence of recognized cryptococcal IRIS did not differ significantly between the earlier-ART group and the deferred-ART group (20% [17 of 87] and 13% [9 of 69], respectively; P=0.32) (Fig. S1 in the, available at NEJM.org). As expected, CD4 cell counts and virologic responses differed during the first month after randomization (with and without ART), but values converged by 26 weeks (Fig.

Earlier ART did not increase the rate of cryptococcal clearance in CSF; early fungicidal activity was −0.31 CFU per milliliter per day in both treatment groups (95% CI, −0.33 to −0.28; 166 participants), with similar rates of CSF culture positivity at 14 days (37% in the earlier-ART group and 39% in the deferred-ART group, P=0.87). Among 59 participants with positive CSF cultures at 14 days, the median cryptococcal growth was 100 CFU per milliliter (interquartile range, 15 to 500), with no significant difference between treatment groups (P=0.13); only 5 participants had more than 10,000 CFU per milliliter in CSF. Adverse events were frequent and primarily attributable to amphotericin, and the rates did not differ significantly between the treatment groups (Fig. S3 and Table S1 in the ).

Thus, earlier ART initiation did not have any advantages over deferred ART initiation with respect to secondary end points. Causes of Death The causes of death were similar in the two treatment groups, with the exception of an excess of cryptococcal meningitis–related deaths in the earlier-ART group (19, vs. 10 deaths in the deferred-ART group). The other causes of death in the earlier-ART group and deferred-ART group, respectively, were bacterial sepsis (9 and 7 deaths), tuberculosis-related causes (2 and 2), IRIS-related causes (1 and 2), cryptococcal meningitis relapse (0 and 2), adverse events due to medication (2 and 0), pulmonary embolism (2 and 2), hypokalemia or hypovolemia (0 and 1), and unknown causes (2 and 3); causes of death reported only in the earlier-ART group were toxoplasmosis (1), intracranial pressure (1), head trauma (1), and multifactorial causes (1). Twenty-seven postmortem examinations were performed (for 39% of deaths), and external adjudication was in agreement with 88% of clinician-ascertained cryptococcal meningitis–related causes of death, with disagreements reconciled after review of additional clinical and postmortem data. Thirteen cryptococcal meningitis–related deaths occurred between 2 and 5 weeks after diagnosis (10 in the earlier-ART group and 3 in the deferred-ART group) and were judged to be caused by the initial cryptococcosis rather than separate, distinct cryptococcal-IRIS events.

Of the 10 patients who died from cryptococcal meningitis–related causes in the earlier-ART group between 2 and 5 weeks after diagnosis, 5 had CSF opening pressures below 250 mm of water at their last lumbar puncture, and 7 had decreases greater than 3 log 10 CFU of cryptococcus per milliliter in their CSF cultures. Thus, clinically it is unclear whether these excess deaths in the earlier-ART group were directly due to sequelae of cryptococcal meningitis or due to IRIS. CSF White-Cell Count Earlier ART did have a detectable effect on the immune response in CSF. At day 14 of amphotericin treatment, the proportion of participants who had CSF white-cell counts of 5 per cubic millimeter or higher was greater with earlier initiation of ART (median, 6 days of ART) than with deferred initiation (58% vs. 40%, P=0.047). The difference was accounted for by an influx of CSF white cells in 10 of the 23 participants (43%) in the earlier-ART group who did not have CSF pleocytosis at diagnosis, as compared with none of the 20 participants without pleocytosis in the deferred-ART group, who were not yet receiving ART (P=0.001).

With earlier ART, it was difficult to determine whether deterioration early after randomization was due to cryptococcal IRIS or to progressive sequelae of cryptococcal meningitis. Nevertheless, earlier ART initiation was associated with significant excess mortality. Discussion This multisite randomized trial showed that deferring ART until 5 weeks after the start of amphotericin therapy improved survival rates among patients with cryptococcal meningitis, as compared with initiating ART at 1 to 2 weeks. This improved survival associated with deferring ART was observed in patients with advanced HIV infection, including patients with severe disease, such as those with CD4 cell counts of less than 50 per cubic millimeter, altered mental status, or lack of CSF pleocytosis. The higher short-term mortality observed with earlier ART initiation in this trial may relate to the site of infection in the anatomically constrained CNS. This adverse effect of earlier ART after cryptococcosis may involve unrecognized increases in inflammatory responses in the CNS due to ART-associated immune reconstitution in the first month after ART initiation. Earlier ART also does not appear to be beneficial in the treatment of HIV-associated tuberculous meningitis.

In contrast to these meningitis results, earlier ART has been shown to reduce AIDS-defining events and deaths in a group of patients with various opportunistic infections, as well as among persons with noncerebral tuberculosis who had CD4 cell counts of less than 50 per cubic millimeter. Thus, the outcomes and consequences of CNS infections, such as cryptococcal and tuberculous meningitis, differ from those of other AIDS-related opportunistic infections, in that earlier ART can be detrimental in CNS infections but can be beneficial overall in non-CNS opportunistic infections. We observed the highest risk of death with earlier ART among participants with low numbers of CSF white cells at randomization. A paucity of CSF white cells has previously been reported as a significant risk factor for cryptococcal IRIS. In tuberculosis, earlier ART is associated with a risk of IRIS that is three to six times as high as the risk associated with deferred ART; however, unlike cryptococcal IRIS, tuberculosis IRIS outside the CNS is rarely fatal. Therefore, we hypothesize that earlier ART is most harmful in high-risk persons with a predisposition to cryptococcal IRIS (i.e., those without CSF inflammation) and that this effect drove the overall results of our trial.

IRIS with CNS infections initiates local inflammation in a confined space, within intracranial structures that are permissive neither to inflammation nor to compression. Persons who have not fully recovered from their initial meningitis episode may not survive a second insult due to IRIS. A limitation of the IRIS case definition is the requirement for previous clinical improvement. For the earlier-ART group, clinicians and the adjudication committee were often unable to discern whether progressive clinical deterioration was due to complications of cryptococcosis or to cryptococcal IRIS, which probably resulted in an ascertainment bias, with underdetection of early IRIS events. Conversely, the cryptococcal IRIS case definition performed well for later IRIS events, in scenarios in which patients had clinical improvement, started to receive ART, and then had clinical deterioration. The differences in mortality between the two treatment groups were of sufficient magnitude that the trial was stopped early by the data and safety monitoring board. As a result, the treatment groups in the COAT Trial did not reach the proposed cohort size.

Historically, trials stopped early have routinely overestimated the magnitude of benefit or harm. Moreover, the smaller sample limits the power for subgroup analyses to provide customized guidance for care of individual patients. This limitation is particularly notable for study participants with CSF pleocytosis, for whom definitive guidance on ART initiation was not determined; however, earlier ART was not beneficial in our analysis. Nevertheless, we believe the main finding of this multisite treatment-strategy trial is generalizable to affected persons in resource-limited and high-income countries. COAT Trial participants received a high level of care from experienced clinicians.

Persons presenting with suspected meningitis underwent lumbar puncture promptly, and comprehensive CSF diagnostic tests were performed with standardized checklists. Intracranial pressure was monitored routinely, and elevated pressure was managed with a median of three therapeutic lumbar punctures during hospitalization. A strength of the trial was the extensive inpatient HIV counseling with systematic linkage to outpatient care; 99% of patients were retained in care as outpatients. The survival rate in both treatment groups was improved as compared with our historical prospective experience with the use of amphotericin and the same deferred-ART regimens (6-month survival rate, 40 to 50%).

Indeed, the improved outcomes in this trial suggest that increased survival is possible in resource-limited settings. However, earlier ART initiation during hospitalization does not improve survival. Supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID; U01AI089244, K23AI073192, T32AI055433, and K24AI096925), the Wellcome Trust (081667 and 098316, to Dr. Meintjes, and 087540, to Dr. Meya), and the Veterans Affairs Research Service (to Dr. Provided by the authors are available with the full text of this article at NEJM.org. Trinh Ly, Dr.

Chris Lambros, Karen Reese, and Dr. Neal Wetherall for their support; Drs. Tihana Bicanic, Lewis Haddow, and Jason Baker for serving on the external adjudication committee; Professors Jim Neaton, Thomas Harrison, John Perfect, and Philippa Easterbrook for providing input on study design and clinical care; Drs.

Alex Coutinho, Aaron Friedman, Moses Kamya, and Robert J. Wilkinson for providing institutional support; Dr. Anne Marie Weber-Main for critical review of a previous draft of the manuscript; the Infectious Disease Institute DataFax team of Mariam Namawejje and Mark Ssennono for data management with support from Kevin Newell, Steven Reynolds, and the staff of the NIAID Office of Cyberinfrastructure and Computational Biology; and the clinical and administrative staff of the Provincial Government of the Western Cape of South Africa for their support.

References • 1 Jarvis JN, Meintjes G, Williams A, Brown Y, Crede T, Harrison TS. Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases. BMC Infect Dis 2010;10:67-67 • 2 Durski KN, Kuntz KM, Yasukawa K, Virnig BA, Meya DB, Boulware DR. Cost-effective diagnostic checklists for meningitis in resource-limited settings. J Acquir Immune Defic Syndr 2013;63:e101-e108 • 3 Cohen DB, Zijlstra EE, Mukaka M, et al.

Diagnosis of cryptococcal and tuberculous meningitis in a resource-limited African setting. Trop Med Int Health 2010;15:910-917 • 4 Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa. GERMS-SA annual report 2012. Johannesburg: National Institute for Communicable Diseases (). • 5 Hakim JG, Gangaidzo IT, Heyderman RS, et al.

Impact of HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients. AIDS 20-1407 • 6 Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009;23:525-530 • 7 French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 20-1038 • 8 Liechty CA, Solberg P, Were W, et al.

Asymptomatic serum cryptococcal antigenemia and early mortality during antiretroviral therapy in rural Uganda. Trop Med Int Health 2007;12:929-935 • 9 Lawn SD, Harries AD, Anglaret X, Myer L, Wood R. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS 20-1908 • 10 Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis.

N Engl J Med 2011;365:1471-1481 • 11 Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011;365:1482-1491 • 12 Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretro.

Mche: I'm going to assume you are a Chemical Engineer. As such, then, I also presume you are talking about Process design - as opposed to mechanical design. This is important to distinguish because H2 makes a big differnce in the mechanical design and very little difference in the process design.

For Process Design, you basically design a Hydrogen pipeline just as you would any other gas. The fundamental and basic guideline to all gas lines is the allowable (or design) pressure drop. Normally that is the key (& oftentimes) the optimum design level to base your calculations on. If you were questioned for basis, state your scope of work - which you should have generated before any attempts to resolve the problem(s).

Use the recognized velocities as they obviously will drop out when you design around the allowable pressure drop. You have to stay sub-sonic in velocity, so that gives you an automatic ceiling value to design from. Always resort to recognized, acceptable standards such as the NORSOK process standards. Norsok recommends that in lines where pressure drop is not crtical, gas velocity should not exceed limits that may create noise or vibration problems.

A rule-of-thumb velocity is given as: V = 175 (1/Den)^0.43 where, V = Max velocity to avoid noise, m/s Den = gas density, kg/m^3 Norsok also lists recommended velocities if you lack these. To download their complete process design standards, go to: I hope this helps. Art Montemayor Spring, TX RE: Hydrogen service lines (Chemical). Montemayor, You guessed it correctly, I needed answer from Process Design point of view which I got from above.

However I am curious about impact of hydrogen on mechanical design also. Is there anything additional, that Process Engineer can do than mentioning presence of Hydrogen and its concentration in the service? (for material selection and fabrication procedure control?) Could you please suggest some readings as to know why 'H2 makes a big differnce in the mechanical design' and are there any guidelines, when it should be higlighted to Mechanical design? Preferably on internet or Codes. Thanks RE: Hydrogen service lines (Chemical) 13 Apr 04 23:58. Mche: As we both know, Hydrogen is the smallest molecule in the Cosmos.

It will literally permeate through anything, if given enough time to do so. It goes through steel pipe walls and if you have ever operated and maintained a Hydrogen system, you will have experienced the fact that when you D&R (Demolish & Remove) old carbon steel Hydrogen piping, you cannot go in and burn out the pipe without first allowing the H2 soaked into the walls to evaporate out. If you don't, the pipe seems to 'catch fire' when the cutting torch heats it up. Bulbul Kannada Movie Songs Free Download Southsongs4u. Hydrogen also has a negative effect on steel that is titled 'embrittlement' - a process that weakens the parent metal to the point of failure. The higher the temperature and pressure of the H2, the more pronounced are the negative effects.

I don't have my materials library here handy at the moment but I recall that we were using a chrome-steel alloy on piping for H2 service back in 1970. There may be other aspects to H2 materials of construction that you should bear in mind, but those two particularly come to mind. I personally have always butt-welded all my H2 piping, reducing the quantity of flanges or possible leaks down to zero - if possible. If you have ever seen (it would have to be at night) a self-ignited H2 leak through a flange gasket, you will wind up doing the same.

Hydrogen will always leak -to begin with- and what's worse is that the stuff has a negative Joule-Thomson value: it heats up when it expands. It also self-ignites with the expansion friction created and the leak catches fire. The way we found most H2 leaks in Steam Reformer units and Hydrogenation plants was to walk out at night and keep an eye out for the bright, whitish flame that H2 gives. You can't see it in the daytime and, in fact, we had an operator severly burned by walking on a catwalk besides a Hydrogen line where there was a leaking flange. He never saw the flame as he walked by and had his arm burned just as if it had been a cutting torch.

You are right on track in keeping your Mech. Engineers fed with as much process information as you can give them. They can only design the mechanical end to the same degree of information that they can gather on H2. Some of the M.E.' S should already know a lot of the H2 characteristics, but it's always wise to work together as a team to produce the safest, most flexible, and most cost-effective installation.

There should be a lot of information out on the Web regarding Hydrogen piping, handling and materials of construction. I know books have been written on the subject.

I can't come up with a list of them, but I know they have existed. I optimistically would expect some of my colleagues on this forum to pitch in additional or further information in accordance with their experience in this field. I hope this has been of help. Art Montemayor Spring, TX RE: Hydrogen service lines (Chemical) 14 Apr 04 10:21. I'd like to clarify one point on hydrogen's wall-penetrating characteristics, by saying it's not only the size of the molecule but -even of more importance- the mass of the molecule than enables it to effuse or diffuse through solid-like walls. If my sources are correct, hydrogen is, in fact, the smallest diatomic molecule (diameter~1.5*10 -10m) and the lightest around.

Helium, a monoatomic molecule, although heavier than the hydrogen molecule, seems to have even a smaller diameter of ~0.98 Angstrom. 1 Angstrom=10 -10m. Effussion rates are inversely proportional to the square root of the molecular mass not volume. Handbook For Arkansas Municipal Officials In The Philippines. This is known as Graham's Law. Thus, hydrogen would penetrate (diffuse) more easily through the pores of a solid wall.

This is explained by the fact that lighter (i.e., of lower mass) molecules move faster and strike the wall more often increasing the chances to move across. RE: Hydrogen service lines (Mechanical) 14 Apr 04 11:17.

I suggest you read some established design standards specific to hydrogen service, such as the NASA or GE standards. You do not want to learn by mistake with this gas. For example: a) NASA does not allow a buried H2 line- if it leaks, it will permeate into any unpressured pipe ( ie sewer line) and result in a fire hazard someone's building.

If needed to be below grade, they recommend a trnech with grating. Although most outdoor combined cycle plants with H2 cooled generators ignore this provision, but be sure to avoid running the pipe near an unpressured line (drain or sewer) b) Nasa recommends that if run overhead in a pipe rack, it be the highest pipe, so if it leaks, it will not burn any above laying component. C) When H2 burns, it cannot be detected by visual cues or radiant heat, as it burns invisibly with near zero emmissivity.

The only safe method of finding the leak is to proceed with a hay broomstick ahead of you or throw sawdust ahead of you ( this recommendation is from the people that flew to the moon!) d) GE provides recomended types of piping material and joining techniques, and allowable sealants. Also, specific valve desigs that are proven safe with H2. E) when passing into a building, use of a double wall pipe ( inner annulus vented to outside). Building roof vent fans to be explosion proof.

Cieling high points to have H2 detectors and vents. RE: Hydrogen service lines. There are several material and design conditions that need to have someone with the knowledge base of particular design considerations of a system containing hydrogen. As mentioned there is the H2 embrittlement concerns and along with this is very important consideration of H2 Induced Fatigue in cyclic services. There is an often overlooked design consideration with H2 in severe cyclic service, as in a PSA system used for H2 purification, of H2 Assisted Fatigue. Someone correct me if needed, I believe there is material selection chart based on H2 partial pressures chart from Nace and also one from Shell Oil.

Anecdotal, but an important consideration. The H2 Assisted Fatigue problem got us really bad in PSA system for a H2 plant.

We had the first failure that was actually examined metallurgically to determine the cause. Ultrasonic examination of the remaining vessels revealed fatigue cracking in all but 4 of the remaining vessels I was fortunate in the fact that I got to see all the small details and even had a sample of a 17' long H2 “Assisted Fatigue” crack, 7' long 1.125' wall penetration from an operating vessel that I was able to procure by convincing management that it was essential to cut in patch and not repair the crack. At the time is was the only one in the world available from an operating vessel and available for metallurgical examination. It went all over the world.

It was a very enjoyable time. All vessels were replaced on an expedited schedule with HIC resistant steel, hemispherical heads and very smooth weld roots. There had been several failures at different locations but none had been metallurgically examined. One of my colleagues had appraised a large chemical company in England that had three similar systems. On Wednesday they had no failures in any of their vessels. The following Monday we got a call that the head to shell weld on a vessel had failed, within several weeks they had two additional failures.

The commonality of the vessels other than the similar design conditions were they were all about 17 years old. On checking with two additional companies, both had failures in 17 year old vessels. The failure mechanism had taken quite a few years to progress about.125' while the last inch had taken only a few days.

In dealing with H2 and have any doubt get some help. RE: Hydrogen service lines (Mechanical) 16 Apr 04 10:43. All: My intent here is not to lengthen this thread, but MJCronin's input, unclesyd's remarks, and jay165's timely reminder of the Nelson Charts point to the seriousness of this subject and what I failed to include in my first post (albeit, due to a lack of resources at the time). The above colleagues have delivered what I was unable to come up with originally and I thank them. An excellent discussion on some of the concerns with Hydrogen corrosion and effects on materials can be found at: I hope that the original poster, Mche, has understood what I was trying to expound: the mechanical design of H2 systems is far more important to consider than the process design. This is an area where Chemical Engineers need a thorough 'dousing' into mechanical design and skills. The difference between a ChemE and an MechE should be nil or nothing when considering the skills that both can impart to a safe and efficient H2 system.

It has been my experience in the past that ChemE's have tended to separate themselves from their MechE brethren, preferring to remain in a 'process area', when they should be doing the opposite and learning more about Mechanical expertise that is so essential to achieve a professional engineering level. An engineer can only enrich himself and his abilities when he actively learns from the other disciplines.

This appliation is an excellent example where both skills need to be firmly integrated to ensure total success. My thanks to all for making up for my initial deficiencies. Art Montemayor Spring, TX RE: Hydrogen service lines (Mechanical) 22 Apr 04 09:32. Art: Amen brother! You're preaching my religion!

As a chemical engineer, I've benefitted immensely from learning more about mechanical and electrical/instrumentation engineering. Likewise, mechs can benefit from learning a little chemistry too, especially if they're practicing in the chemical process industry. A combined team is best, but the team only works well if all parties understand where the others are coming from.

Cross-disciplinary skills are very, very important to the engineering of a safe product. RE: Hydrogen service lines (Chemical).

Following I note from various references I could read in last few days. If a process engineer has to participate in design of a system where hydrogen is one of the components then he/she should, at least, 1.Specify hydrogen partial pressure in process data sheet 2.Based on operating temperature and hydrogen partial pressures verify the selected material. (Reference, API 941 be used.) 3.Verify for mechanical design that PWHT is specified. There may be lot more as I am knowing more about the subject but I feel this is bare minimum. RE: Hydrogen service lines (Chemical) 23 Apr 04 02:15.

As a former GE engineer responsible for the design of their H2 cooling system auxiliaries, for H2 cooled generators, one of the most important safety features is in the compatibility of the system devices, valves, instruments, gaskets and all other wetted parts. Davefitz's reference is close, but the spec isn't intended to be based around a vendor or valve type (ball vs. Globe, etc.). Rather it's regarding the 'flameproof' requirement on all H2 system valves. 'Flameproof', in the valve world, means that the valve will have a secondary mechanical and metallic seat that will help prevent the emission of H2 in the event of an 'ambient' fire. This prevents the H2 from 'feeding the flame' so to speak.

Many of the GE specs were actually functional specs submitted to sub-vendors. It then became the vendor's responsibility to implement the proper industry standards for these systems.