Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012". DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy wasdeveloped at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroupsand among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.(AU)

Use of ANOVA to estimate inter- and intra-reader variability for a group of readers in thorough QT/QTc studies.

The E14 guidelines of the International Conference on Harmonization require that all new drugs that have systemic bioavailability be subjected to a thorough QT/QTc study to look for possible effects on cardiac repolarization. Recent publications have discussed various aspects of thorough QTc studies. The thorough QTc study is designed to detect a mean drug-induced QTc prolongation of >5 ms with an upper bound of the 95% one-sided confidence limits of >10 ms. The E14 guideline has spelled out the procedures to be followed in a thorough QT/QTc study, including choice of subjects, methods of electrocardiogram (ECG) acquisition, details of ECG analysis, and statistical analysis of the study data. Since the measurement of the QT interval is a relatively subjective assessment, the ECGs must be analyzed in a central ECG laboratory by "a few skilled readers." In order to maintain quality in ECG interpretation, the E14 guidelines have two requirements. First, as a measure of the assay sensitivity, the study must include an active control known to prolong the QTc interval. Second, a certain percentage of ECGs must be subjected to an inter- and intra-reader variability analysis; these data are submitted to the regulatory authorities along with the study results.

Captopril in the treatment of cardiovascular manifestations of indian red scorpion (Mesobuthus tamulus concanesis Pocock) envenomation.

OBJECTIVES: To study outcome of patients with scorpion envenomation treated with oral captopril in the ICU of a Tertiary Care, University Hospital in Mumbai. METHODS: Retrospective analysis of all patients with scorpion sting admitted to Medical Intensive Care Unit of a tertiary care university hospital in Mumbai between 1993 and 2003. RESULTS: Of 38 patients with cardiovascular manifestations, six had tachycardia alone and 8 had hypertension; these patients received oral captopril 12.5-25 mg thrice daily with no deaths. Pulmonary oedema with normal blood pressure and high central venous pressure (CVP) was seen in 10 patients. Five patients had hypotension, low CVP but no pulmonary oedema; with fluid infusion, these patients had correction of low CVP and hypotension, but developed pulmonary oedema. Pulmonary oedema resolved in all 15 patients with captopril (6.25-25 mg thrice daily): one patient died of ventricular tachycardia. Nine patients had cardiogenic shock; 6 patients, whose blood pressure improved with dopamine received, captopril; 1 of these 6 died. The other three patients did not respond to maximum vasopressor therapy and could not be given captopril; all three died. Four of the 5 deaths occurred in patients weighing < 25 kg suggesting that severity of cardiovascvlar manifestations also depends on body weight of the victim. CONCLUSION: Afterload reduction with oral captopril is safe and effective in scorpion envenomation with cardiovascular manifestations. Results are similar to those with other vasodilators.

Heparin or local thrombolysis in the management of cerebral venous sinus thrombosis?

SUMMARY: Patients with acute cerebral venous sinus thrombosis treated with Heparin or in situ thrombolysis in our department were evaluated in an attempt to rationalize treatment with heparin or thrombolysis. 279 patients with angiographically proven acute cerebral venous sinus thrombosis were included in the study. Patients were classified into mild and severe clinical grade. The study was divided into three phases. Phase I included 27 patients treated with systemic heparin. Phase II included 72 patients, 30 in severe grade and 42 in mild. 26 were thrombolysed with 14 in severe and 12 in mild grade. Phase III included 180 patients treated according to a defined protocol. 133 were in mild grade and 47 in severe. 67 patients were thrombolysed. In the thrombolysed group 27 patients were in mild grade and 40 in severe. 113 patients were treated with systemic heparin. Following acute management all were anticoagulated for six months. The baseline characteristics were found to be same in all three phases. On comparison of outcome in Phase III with Phase 1 the likelihood ratio was found to be statistically significant in favor of Phase III (p<0.0001). The likelihood ratio was found to be statistically significant in mild and severe clinical grade in favor of thrombolysis in Phase III (p 0.039 in mild and p 0.00001 in Severe clinical grade). This ratio was insignificant (p=0.716) for intracranial bleed; however, local puncture site bleeding was found to be significant in the thrombolysed group (0.00005).

A prospective study evaluating the efficacy of a single, 45-mg dose of primaquine, as a gametocytocidal agent, in patients with Plasmodium falciparum malaria in Mumbai, India.

The efficacy of a single dose of 45 mg primaquine, as a gametocytocidal agent, was assessed in Mumbai, India, among adults with uncomplicated or severe Plasmodium falciparum malaria. All the patients investigated had been found gametocytaemic, with at least 56 gametocytes/microl blood, within the first 72 h of their illness. Those with uncomplicated malaria, like those with severe malaria, were randomized to receive or not receive primaquine. All the patients were followed up for 29 days post-admission, for gametocytaemia and gametocyte viability (as determined by exflagellation). Among those with uncomplicated malaria, six (27.3%) of the 22 who did not receive primaquine but only one (4.2%) of the 24 who did receive the drug, on day 4, remained gametocytaemic on day 29 (P < 0.05). Similarly, seven (31.8%) of the 22 severe cases who did not receive primaquine but only two (9.5%) of the 21 severe cases who received the drug, on day 8, were found gametocytaemic on day 15 (P < 0.05). While the single, 45-mg dose of primaquine recommended by the World Health Organization was effective in clearing gametocytes from the blood of > 90% of the present cases of malaria, > 4% of the patients with uncomplicated malaria and > 9% of those with the severe disease continued to harbour gametocytes in their peripheral blood 29 and 15 days after taking the primaquine, respectively.

Benzathine penicillin, metronidazole and benzyl penicillin in the treatment of tetanus: a randomized, controlled trial.

Penicillin, the drug of choice in tetanus, may potentiate the effect of tetanus toxin by inhibiting the type-A (GABAA) receptor for gamma-amino-n-butyric acid. Metronidazole has therefore been suggested as an alternative. Intramuscular benzathine penicillin (1.2 million units as a single dose; N=56), enteral metronidazole (600 mg every 6 h for 10 days; N=55) and intravenous benzyl penicillin (2 million units every 4 h for 10 days; N=50) were therefore compared, in a randomized, controlled trial, among patients with all grades of tetanus. On presentation, the three treatment groups were similar in terms of age and sex distributions, immune statuses, durations of illness, and their APACHE-II scores and Ablett's grades of tetanus. Of the patients given benzathine penicillin, 36 required tracheostomy, 10 neuromuscular blockade, and 23 mechanical ventilation; the corresponding numbers for the metronidazole (34, 12 and 18, respectively) and benzyl-penicillin groups (39, 12 and 25, respectively) were similar (P>0.10). The incidences of dysautonomia and nosocomial pneumonia and the numbers of in-hospital deaths (26 with benzathine penicillin, 19 with metronidazole and 22 with benzyl penicillin; P=0.392) were also similar in each treatment arm. The length of the hospital stay was longer in the patients receiving benzyl penicillin than in the benzathine-penicillin or metronidazole groups, with means (S.D.) of 21.9 (15), 16.9 (11) and 19.9 (15) days, respectively, but the difference was not statistically significant (P=0.09). Although the three antibiotic regimens investigated appear equally effective, benzathine penicillin offers the convenience of a single, intramuscular injection instead of the 10 days of therapy needed with the other two drugs.

Cerebral venous and dural sinus thrombosis in severe falciparum malaria.

Common causes of coma in falciparum malaria are cerebral malaria, hypoglycaemia and electrolyte disturbances. Focal deficits due to arterial infarcts may sometimes occur in children, but are rare in adults. Three adults with falciparum malaria who had fever, altered consciousness and focal neurological deficits (one of whom also had seizures) are being reported here. CT scan of the brain revealed haemorrhagic infarction of the cerebral cortex and subcortical white matter with surrounding oedema suggestive of venous infarction in all three patients. The diagnosis of cerebral venous thrombosis was missed in the first patient, and was detected only at autopsy. In the next two patients, superior sagittal sinus thrombosis was confirmed angiographically. Only one patient survived; the other two died of increased intracranial pressure. Two of the three patients also had Plasmodium vivax co-infection. A hypercoagulable state resulting from severe malaria may be responsible for this rare and potentially fatal complication. Cerebral malaria may be associated with raised intracranial pressure due to cerebral oedema. Cerebral venous thrombosis may worsen this and adversely affect outcome. This diagnosis should be suspected in patients with severe malaria who develop focal neurological deficits and confirmed by appropriate imaging; judicious use of local thrombolytic therapy may help improve outcome.

Diagnostic and prognostic utility of rapid strip (OptiMal and Paracheck) versus conventional smear microscopy in adult patients of acute, uncomplicated P. falciparum malaria in Mumbai, India.

OBJECTIVES: The present study compared the diagnostic and prognostic utility of two rapid tests the (Paracheck and OptiMal) versus conventional smear microscopy. METHODS: Using two independent microscopists we carried out the three tests in 31 adult cases of smear positive, acute, uncomplicated Plasmodium falciparum malaria. All three tests were done pretreatment, and on Days 8, 15 and 29. RESULTS: Compared to microscopy, the Paracheck had a sensitivity of 100%, while the OptiMal had a sensitivity of 83.7%. The lower sensitivity of OptiMal resulted from misidentification by both microscopists of 6/31 cases as Plasmodium vivax. As a follow up tool, the OptiMal was better than Paracheck, due to the earlier disappearance of the parasite LDH. Also in the Paracheck, between microscopists, there was a significant difference in reading the tests, on Days 8 and 15. CONCLUSION: Our study reiterates, the continued utility of conventional smear microscopy.

Predicting the reduction of parasitaemia following exchange transfusion in severe Plasmodium falciparum malaria: comparison of two mathematical formulae.

Two mathematical models to predict the level of parasitaemia after exchange transfusion in severe malaria have been described. One formula, described by Wilkinson and colleagues, calculates the level from the total volume of blood exchanged whereas the other, derived by Van den Ende and colleagues, is recursive and gives estimates of the reduction in parasitaemia after each aliquot of exchange. The accuracies of predictions based on these two formulae were compared using data collected from 20 patients undergoing partial exchange transfusion (40 ml blood/kg body weight). The transfusions led to significant changes in the mean (S.D.) haemoglobin concentrations, which rose from 8.9 (2.4) to 10.1 (1.5) g/dl, and in the median levels of parasitaemia, which fell from 16.5% (interquartile range = 12.8%-28.8%) to 4.5% (interquartile range = 1.2%-9.3%). The median level of post-transfusion parasitaemia predicted by the Van den Ende formula (6.6%, with an interquartile range of 4.5%-10.2%) was similar to that observed, whereas that predicted by the Wilkinson formula (7.2%, with an interquartile range of 5.6%-12.4%) was significantly higher (P = 0.018). However, the median difference between the predictions based on the two formulae was represented by a parasitaemia of only 1.0% (interquartile range = 0.6%-1.85%). Thus, although the Van den Ende formula is more accurate than the Wilkinson, the difference is unlikely to be clinically significant.

Human immunodeficiency virus type 1 infection in patients with severe falciparum malaria in urban India.

BACKGROUND: CD4+ T cells restrict parasitaemia during the first attack of falciparum malaria; humoral immunity, develops weeks later and protects against reinfection. HIV infection may affect severity of falciparum malaria and development of protective immunity. AIMS: To study the prevalence of HIV infection in Indian patients with severe falciparum malaria and its effect on severity of illness and recurrences of and mortality related to malarial infection. PATIENTS: Consecutive patients with severe falciparum malaria and voluntary blood donors. SETTING AND DESIGN: Prospective cohort study in a university hospital in Mumbai. RESULTS: Five (11.6%) of 43 patients and 521 (1.8%) of 28749 blood donors had HIV infection (OR 7.1, 95% CI = 2.8 to 18.2, p=0.001). Clinical features, APACHE II score, number of organs affected, parasite index and mortality in patients with and without HIV infection were comparable. CD4+ counts were < 500 cells/ microl in 2 patients and normal in 3. Opportunistic infections including pulmonary tuberculosis in one patient (CD4+ counts > 500 cells/ microl), and oral candidiasis in two (CD4+ counts 275 and 250 cells/ microl) were noted. One patient developed fatal Pneumocystis carinii pneumonia two weeks after recovering from malaria. P. falciparum infection recurred in 2 of the 4 HIV infected survivors and in none of 31 survivors without HIV infection (RR 38.8, 95% CI 2.2 to 671, p=0.01). CONCLUSIONS: HIV infection is associated with increased risk of severe malaria even with normal CD4+ counts; severity of disease and mortality are not increased. However, prior HIV infection impairs protective immune response to Plasmodium falciparum in residents of hypoendemic areas.

Deferiprone (L1) as an adjuvant therapy for Plasmodium falciparum malaria.

BACKGROUND & OBJECTIVES: Mortality due to Plasmodium falciparum infection remains high in India, hence any modality of treatment which can improve the outcome of this disease is worth exploring. The present study was undertaken to see whether addition of an oral iron chelator, deferiprone (L1) to the conventional treatment regime for P. falciparum infection improves the clinical course and final outcome. METHODS: In this prospective, randomised double blind trial, 45 consecutive patients with P. falciparum infection were randomised into two groups. Patients in Group I (control group, 21 patients) received standard quinine and doxycycline therapy along with supportive therapy and placebo capsules for 10 days. Patients in Group II (24 patients) received the same treatment as Group I but in place of placebo capsule received deferiprone capsules 75 mg/kg/day in 12 hourly divided doses. The parameters evaluated included the time taken in resolution of parasitaemia, fever and coma, differences in final outcome i.e., death or other severe complications, and side effects and deferiprone tolerance. RESULTS: Four patients in Group I and two in Group II died (P > 0.05). The resolution of fever and coma was significantly faster in Group II (P < 0.05) and parasitaemia cleared 24 h earlier in this Group. The drug was well tolerated and had no side effects. INTERPRETATION & CONCLUSION: Deferiprone (L1) seems to be a promising agent as an adjuvant in the treatment for severe P. falciparum malaria infection.

Anti-neutrophil cytoplasmic antibodies (ANCA) in malaria.

Various autoantibodies like anti-nuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA), anti-histone antibodies (AHA), anti-neutrophil cytoplasmic antibodies (ANCA), anti-myeloperoxidase (anti-MPO), anti-proteinase3 (anti-PR3) and anti-lactoferrin (anti-LF) antibodies were studied in 173 acute hospitalised patients suffering from malaria of which 160 patients had P. falciparum and remaining 13 had P. vivax infection. Standard methods like indirect immunofluorescence (IIF) microscopy along with Confocal microscopy and ELISA were used for identifying and quantifying the autoantibodies and IIF patterns on PMN and HL-60 cells were studied for ANCA classification. Also HEp-2 cells were used for ANA detection, while estimation of anti-dsDNA, AHA, anti-MPO, anti-PR3 and anti-LF were tested using ELISA. Sera from malaria patients showed prominent immunofluorescence staining patterns where 23.8% cases had ANA in P. falciparum group as compared to 15.4% in P. vivax group and ANCA was found to be present in 20% in P. falciparum and 15.4% in P. vivax group. An interesting observation was that, of the total ANCA positives, 59% had p-ANCA, 5.9% had c-ANCA and 44.1% of the cases showed the 'atypical' or X-ANCA pattern. When p-ANCA positivity was compared with c-ANCA positivity among these patients, a good statistical correlation was noted with OR = 16, chi 2 = 16.43, EF = 0.46 and p-value = 5.037E 0.5. ELISA showed 31.2% anti-MPO and 6.2% anti-PR3 in P. falciparum cases while the two ANCA positive cases in P. vivax had anti-MPO. Anti-LF was found to be present in 40.6% cases. Neither the P. falciparum nor P. vivax contained autoantibodies with specificities similar to the characteristic lupus autoantibodies such as double stranded DNA (dsDNA). ANCA positivity develops in some types of malarial infection also with the presence of various autoantibodies which is important from a clinical point of view and should be carefully evaluated in those geographic areas where malaria is endemic. It also alerts us to the fact, whether in cases of repeated malarial infections in susceptible individuals, vasculitic disorders, which through ANCA pathways develop, could lead to renal and other complications.

HLA associations in P. falciparum malaria patients from Mumbai, western India.

In the present study, HLA associations among the cohort of 171 severe P. falciparum malaria patients were compared with that of 101 normal sex, age and ethnically matched control samples. All these individuals lived in Mumbai in an area of low and seasonal P. falciparum transmission. HLA A, B, DRB1 and DQB1 antigens were serologically (A and B) and molecularly (DRB and DQB) determined using isolated lymphocytes and genomic DNA following the microlymphocytotoxicity assay and PCR-SSP techniques. Significant differences were observed between patients with malaria and controls in the following groups of alleles: A3, B27, B49, DRB1*04, and DRB1*0809 were increased, while A19, A34, B18, B37, and DQB1*0203 were decreased. HLA B49 and DRB1*0809 were found to be positively associated with the complicated severe malaria patients (OR = 13.88; p < 0.0001). HLA A19, B5 and B13 were protective in patients with high parasite index (> 2%). These observations revealed the importance of ethnic background, which has to be taken into consideration while developing an ideal malaria vaccine. Further, when compared to HLA associations of other world populations the present study indicates the relative importance of different HLA alleles that may vary in different populations.

Metoclopramide for preventing pneumonia in critically ill patients receiving enteral tube feeding: a randomized controlled trial.

OBJECTIVE: To determine whether metoclopramide prevents nosocomial pneumonia in intensive care unit (ICU) patients receiving enteral feeding by a nasogastric tube. DESIGN: Prospective, randomized, controlled trial. SETTING: ICU of a university hospital. PATIENTS: A total of 305 consecutive patients requiring placement of a nasogastric tube for >24 hrs. INTERVENTIONS: Patients were randomized to receive either 10 mg of metoclopramide or placebo at 8-hr intervals through the nasogastric tube. MEASUREMENTS AND MAIN RESULTS: A total of 174 patients received placebo and 131 received metoclopramide. Baseline characteristics in the two treatment groups were comparable. Of the 305 patients, 46 developed nosocomial pneumonia, which was 24 patients (13.7%) in the placebo group and 22 (16.8%) in the metoclopramide group (p > .05). Patients in the placebo group developed pneumonia earlier than patients receiving metoclopramide (4.46+/-1.72 days [mean +/- SD[rsqb] after ICU admission compared with 5.95+/-1.78 days; p = .006). Subgroup analysis showed that metoclopramide did not reduce the frequency rate of pneumonia in patients with tracheal intubation (19 [25.3%] of 75 patients receiving metoclopramide vs. 21 [21.2%] of 99 patients receiving placebo) or those receiving mechanical ventilation (17 [25.6%] of 58 patients receiving metoclopramide vs. 20 [29.3%] of 78 patients receiving placebo). The mortality rate also did not differ in the two treatments groups (56% in the metoclopramide group vs. 53% in the placebo group; p > .05). CONCLUSIONS: Although metoclopramide delayed the development of nosocomial pneumonia, it did not decrease its frequency rate and had no effect on the mortality rate in critically ill patients receiving nasogastric enteral feeding.

Quality, cost, and outcome of intensive care in a public hospital in Bombay, India.

OBJECTIVE: To study the quality, cost, and benefits of intensive care in a public hospital in Bombay, India. DESIGN: Prospective collection of data. SETTING: Seventeen-bed medical-neurology-neurosurgery intensive care unit (ICU) of a municipal teaching hospital. PATIENTS: A total of 993 consecutive ICU patients during a 16-month period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The 993 patients aged 36.5 +/- 16 yrs (mean +/- SD) had a day-1 Acute Physiology and Chronic Health Evaluation (APACHE) II score of 14.9 +/- 9.6 (mean +/- SD), with a predicted mortality of 21.7%; the observed mortality was 36.2% (standardized mortality ratio = 1.67). The day-1 Therapeutic Intervention Scoring System (TISS) points were 17.7 +/- 6.2 (mean +/- SD), and total TISS points per patient were 87.6 +/- 110 (mean +/- SD). Nurse-to-patient ratio in the ICU was 3:17 and the average workload per nurse was 64.2 TISS points. The average length of stay was 5.5 days (SD = 7.1 days). The overall cost of treating 993 patients was, in Indian rupees (Rs), Rs 107,79,209 (U.S. $307,997), and cost per patient per day was Rs 1,973 (U.S. $57). The cost per survivor was Rs 17,029 (U.S. $487) and cost per TISS point was Rs 90.14 (U.S. $2.57). The low cost per TISS point was attributable to the reuse of disposable equipment and lower cost of drugs and salaries for medical and paramedical staff. CONCLUSIONS: Intensive care in India is cheaper than in the West; however, mortality is 1.67 times that for patients with similar APACHE II scores in ICUs in the United States. This finding may be attributable to the lesser intensity of care per patient (lower day-1 TISS points), lower nurse-to-patient ratio because of shortage of trained personnel and budgetary constraints, and higher workload per nurse (64.2 TISS points per nurse, compared with 40 points per nurse in the West). In addition, the APACHE II scores may underestimate mortality for Indian patients because of differences in case mix, higher lead time between onset of admission and treatment before ICU admission, and possible inappropriateness of age points derived from American patients for Indian subjects because of a higher burden of diseases at lower ages in Indian patients.