in 2009 , cases of influenza like illness were first reported in mexico on march 18 ; the outbreak was subsequently confirmed as h1n1 influenza .
a novel h1n1 swine origin influenza virus has led to a worldwide pandemic 1 . in the affected patients
, a novel swine origin influenza a ( h1n1 ) virus ( s - oiv ) with molecular features of north american and eurasian swine , avian , and human influenza viruses were isolated 2 . in the same month , the world health organization ( who ) classified the global spread of this virus as a public health event of international concern .
after documentation of human to human transmission of the virus in at least three countries of two who regions , the who raised the pandemic level to 6 3 .
it has spread very rapidly since the first cases were diagnosed in mexico with the subsequent spread of the virus throughout europe during the winter season . the h1n1 2009 influenza pandemic ( ph1n1 )
has resulted in over 15921 deaths worldwide more than 212 countries as of 14 february 2010 4 .
turkey reported its first laboratory - confirmed case of influenza a ( h1n1 ) on 16 may 2009 , becoming the eighteenth country in the who european region to do so , and a second case on 17 may 2009 5 . the clinical picture in severe cases of pandemic ( h1n1 ) 2009 influenza is markedly different from the disease pattern seen during epidemics of seasonal influenza , in that many of those affected were previously healthy young people .
current predictions estimate that , during a pandemic wave , 12 - 30 % of the population will develop clinical influenza ( compared with 5 - 15% for seasonal influenza ) with 4% of those patients requiring hospital admissions and one in five requiring critical care 6 . pandemic influenza
a ( h1n1 ) virus infection is the first pandemic in which intensive care units ( icu ) play a fundamental role . during the pandemic ,
, we describe futures of intensive care unit admission , demographic characteristics , treatment and outcome for critically ill patients with laboratory - confirmed and suspected infection with the h1n1 virus admitted to the three different critical care departments during winter of 2009 in turkey .
in response to an outbreak of influenza a virus infection in mexico , turkish ministry of health developed a case report form .
the patients were admitted to hospital and critical care units according to this case report form .
data were collected retrospectively on all patients who had influenza a 2009 related critical illness from november 1 2009 to december 15 2009 .
ethical approval was provided from the ethics committee of meram medical faculty , selcuk university , konya , turkey .
influenza - like illness ( ili ) is defined as fever , cough , and headache , accompanied by one or more of the following signs or symptoms : rhinorrhea , coryza , arthralgia , myalgia , prostration , odynophagia , chest pain , abdominal pain , and nasal congestion .
data were reported by the attending physicians reviewing medical charts , radiologic and laboratory records .
the following information was recorded ; demographic data , comorbidities , time from illness onset to hospital admission , time to first dose of antiviral delivery , microbiologic findings , and chest radiologic findings at icu admission .
intubation and mechanical ventilation requirements , adverse events during icu stay and laboratory findings at icu admission were also recorded .
we classified patients according to case definitions ( confirmed , probable , or suspected ) developed by the world health organization and centers for disease control and prevention . a confirmed case of novel influenza
a ( h1n1 ) virus infection is defined as a person with an ili with laboratory confirmed novel influenza a ( h1n1 ) virus infection by real time rt - pcr 8 , 9 .
we defined critically ill patients as those admitted to an adult intensive care unit ( icu ) ; requiring mechanical ventilation or receiving intravenous infusion of inotropic or vasopressors during the hospitalization .
severity of illness was assessed in adults using the acute physiology and chronic health evaluation ( apache ) ii within 24 hours of icu admission .
we recorded co - morbidities and prior defined major co - morbidities as the presence of one or more of the following chronic medical conditions : asthma , chronic obstructive pulmonary diseases ( copd ) , congestive heart failure , malignancy , neuromuscular disorders , cerebral palsy , diabetes mellitus , coronary artery diseases , heart diseases , chemotherapy , malnutrition , immunosuppressive status or renal failure .
nasopharyngeal - swab specimens were collected at admission , and bronchial - aspirate samples were obtained after tracheal intubation .
specimens were placed in transport medium and kept at a temperature from 2 to 4c .
centers for disease control and prevention ( cdc ) 10 . seasonal vaccination history and radiographic findings
specimens ( bronchoalveolar lavage and blood ) for culture sent to microbiology laboratory for detection of bacterial infection in invasive and noninvasive mechanically ventilated patients .
the body - mass index ( bmi , weight in kilograms divided by the square of the height in meters ) was calculated .
statistical analysis ; descriptive analysis included frequency ( % ) and mean  standard deviation ( sd ) .
during the study period which is november 1 2009 to december 15 2009 , 61 critically ill patients were admitted to three different critical care units in turkey due to confirmed or suspected influenza a 2009 ( h1n1 ) infection were assessed . in 45 patients , diagnosis was confirmed by real - time pcr for pandemic h1n1 virus . in 16 patients , diagnosis was suspected according to cdc and who criteria 8 , 9 .
average age was 41.52  15.7 years and , 54 % were female ( female : 33 , male : 28 ) .
mortality rate in males was 64.3% and in females 39.4% ( p > 0.05 ) clinical characteristics of patients with influenza a virus infection were showed in table 1 , table 2 and table 3 . in table 4 comparison between survivors and nonsurvivors were shown .
symptoms at presentation included fever ( 88.5 % ) , cough ( 83.6 % ) , sputum ( 79 % ) and dyspnea ( 96.7% ) .
diarrhea , nausea , and vomiting were reported in 24.6 % , 39.3 % , and 45.9 % , respectively .
the mean time from the onset of illness to critical care admission was 7.56  4.1 days ( range , 2 to 22 ) .
obesity ( 27.9 % ) and copd ( 14.7 % ) were the most common conditions in patients .
there was no significant difference according to underlying medical condition in between nonsurvivor and survivor groups .
a total of 3 patients ( 4.9% ) were pregnant , of whom 2 had another underlying medical condition ( asthma and heart disease ) .
of the 4 pregnant patients , 1 was in the first trimester , 1 was in the second trimester , 1 was in the third trimester , and 1 was in the postpartum period . at the time of icu admission , all patients had elevated lactate dehydrogenase levels ( 604.8  316.9
u / l ) , 25 ( 40.9 % ) above 500 u / l , and 7 ( 11.4 % ) above 1000 u / l .
thirty - three patients ( 54% ) had elevated aspartate aminotransferase ( 144.5  178.07 u / l ) .
u / l ) . sixteen patients ( 26% ) had increased creatinin kinase levels ( mean 418.7  529.1 u / l ) ( range , 6 to 2573 u / l ) .
c - reactive protein was measured in 48 patients ( 78.7% ) with a mean of 95.1  49.5 mg / dl .
eighteen patients ( 24.6 % ) had elevated creatinine levels ( > 1.2 mg / dl ) at hospital admission . on admission , 11 of 61 ( 18 % ) patients who were tested had leukopenia , 27 of 61 ( 42.2 % ) had anemia , and 18 of 61 ( 29.5 % ) had thrombocytopenia .
the mean time from the onset of illness to the initiation of antiviral therapy was 7.44.17 days ( range , 1 to 22 days ) ; 2 of the patients received antiviral therapy within 48 hours after the onset of symptoms .
antiviral therapy was started before admission in 4 patients , on admission in 55 patients , within 48 hours after admission in 2 patients .
there was significant difference according to the time from the onset of illness to the initiation of antiviral therapy between nonsurvivors and survivors ( p<0.05 ) .
antibiotic therapy was started before admission in 32 patients and on admission in 29 patients .
patients received a mean of two different antibiotics ( range , one to five ) ; 81% of the patients received more than one antibiotic .
commonly used antibiotics included moxifloxacin ( in 19 patients ) , linezolid ( in 14 patients ) , ampicilline - sulbactam ( in 13 patients ) , clarithromycin ( in 13 patients ) , piperacillin - tazobactam ( in 12 patients ) , imipenem ( in 11 patients ) , third generation cephalosporin ( in 9 patients ) , vancomycin ( in 2 patients ) , teicoplanin ( in 4 patients ) , and tigecycline ( in 8 patients ) .
of 61 patients for whom data were available regarding the use of corticosteroids , 20 ( 32.8 % ) received intravenous steroids .
of the patients who received corticosteroids , 85 % had an underlying medical condition ; the most common conditions were copd and asthma ( 70% ) .
patients with viral primary pneumonia had bilateral patchy alveolar opacities , affecting two or five quadrants in 51 patients .
all patients had a mean oxygen saturation of 65% ( range , 45 to 80 ) in the absence of supplementary oxygen .
after supplementary oxygen , all patients had a mean oxygen saturation of 83.7 % ( range , 49 to 98 ) .
mean apache ii score was 18.7  6.3 ( range , 6 to 37 ) .
ards was diagnosed in 48 patients ( 78.6 % ) and ali in 4 ( 6.5 % ) of the patients .
clinical evidence of bacterial infection on icu admission was present in 7 patients ( 11.4 % ) .
data on the use of mechanical ventilation in the icu were available for all patients .
fifteen of these patients were endotracheally intubated after a mean of 3.4  1.7 days .
apache ii score was higher in nonsurvivors ( 20.9  6.7 ) than survivors ( 16.5  5.4 ) ( p<0.01 ) .
there were 8 obese patients in nonsurvivor group and in 7 obese patients in survival group ( p>0.05 ) .
in 3th days , mean level of urea , creatinine , international normalized ratio ( inr ) and heart rate were higher nonsurvivors than survivors ( p<0.05 , p<0.05 , p<0.05 , and p<0.01 ) .
pao2/fio2 ratio was lower in nonsurvivors than survivors in third icu day ( p<0.05 ) .
of all patients , 56 ( 91% ) were mechanically ventilated on the first day of icu admission ; 14 ( 23 % ) patients received invasive and 42 ( 68.8 % ) noninvasive mechanical ventilation .
apache ii score , pco2 , white blood cell count and neutrophil account were higher in invasive mechanical ventilation group than nimv group .
duration of nimv and imv were 5.28  3.4 days ( range , 2 to 14 ) and 6.92  5.8 days ( range , 1 to 19 ) respectively . in survivors ,
the length of invasive mechanical ventilation ranged from 1 to 19 days ( 6.2  5.5days ) .
the length of nimv ranged from 1 to 14 days ( 4.25  3.8 days ) .
there were no significant differences in tidal volume or ventilation strategies between survivors and nonsurvivors .
patients who survived were more likely to have nimv use at the time of admission to the icu .
patients who died were more likely to have imv use at the time of admission to icu .
our data of critically ill patients with influenza a 2009 ( h1n1 ) reveals that relatively younger patients are affected by the disease .
there was a relatively long period of illness prior to presentation to the hospital , followed by a short period of acute and severe respiratory deterioration .
these patients had severe hypoxia requiring high fio2 , peep , and ventilator pressures . within 30 days ,
previously published reports have highlighted cases of severe viral pneumonia affecting patients younger than the expected age of patients affected during a normal influenza season 11 .
the low mean age is different from seasonal influenza , in which older patients appear more susceptible to severe diseases 12 .
importantly , severity of illness and mortality in our cohort are similar to that demonstrated previously with novel h1n1 .
the first data from mexico showed that most of the patients were previously healthy 1 . in our study ,
the most of critically ill patients had comorbidities and there was no difference according to comorbidities between survived and died patients .
a history of lung diseases , obesity , diabetes , hypertension , neurological diseases , malignancy , and heart diseases were the most common comorbidities in our study ( 83.6% ) . among critically ill patients
, obesity has been shown to be a risk factor for increased morbidity , but not consistently with mortality 15 . in our study , there was no statistically significant difference due to obesity between survivors and nonsurvivors .
an early 2009 meta - analysis indicated that obesity was not associated with increased icu mortality 16 . a recent , large cohort study by gong et al .
17 prior to 2009 novel h1n1 infection , noted an association of obesity with ards but not with mortality .
the canadian novel h1n1 experience likewise suggests that bmi did not differ between survivors and non - survivors 18 .
patients with h1n1 infection - related critical illness experienced symptoms for an average of 6 days prior to hospital presentation , but rapidly worsened and required care in the icu within 1 to 2 days 1 . in our study , this duration was higher than other studies 1 , 18 , 19 .
the tendency of females to develop severe 2009 influenza a ( h1n1 ) infection in this series is striking .
a general female susceptibility has been observed in other influenza case series of variable severity including reports of h1n1 infections 18 , 19 . in this report ,
the explanation for increased risk of death among males in this report may be due to existence of more frequent comorbidities in man . in most of infectious diseases and related conditions such as sepsis and septic shock ,
males represent a larger proportion of cases and have a higher mortality 20 , 21 .
importantly , we found in this cohort that apache ii score may help to identify patients at high risk of death . rarely , we used vasopressor support on day 1 following icu admission ( 3.2% ) .
chest radiographs demonstrating bilateral mixed interstitial or alveolar infiltrates were found in 90% of patients . in our study ,
92% of patients required ventilator support for profound hypoxemic respiratory failure , requiring high levels of inspired oxygen and peep . however , survival rate was higher in nimv than invasive ventilation .
noninvasive ventilation has been used an alternative therapy for patients with acute respiratory failure with hopes of obviating intubation and mechanical ventilation .
the results of nimv in hypoxemic respiratory failure have been conflicting , and the etiology of hypoxemia appears to be an important determinant of its success .
22 compared nimv to conventional venture oxygen delivery in patients with severe hypoxemic respiratory failure and found that nimv decreased the need for intubation .
this benefit was observed in the subgroup of patients with pneumonia , but not in those with ards , in which the intubation rates were high in both groups .
a meta - analysis suggests that nimv does not decrease the need for intubation , so there is not enough evidence to support its use in ards 23 . of all patients ,
56 ( 91 % ) were mechanically ventilated on the first day of icu admission ; 14 ( 23 % ) invasively and 42 ( 68.8 % ) noninvasively .
24 reported that invasively ventilation was used in 82.7% of patients . in kumar 's study 18 ,
invasive ventilation was used in 81% of patients with swine flu associated respiratory failure . in our study , we used noninvasive ventilation in 68.8% of critically patients with 2009 influenza a ( h1n1 ) on admission icu . in critically ill patients with 2009 influenza a ( h1n1 ) infection
, high levels of peep were often used to achieve adequate oxygenation . in our study , patients with ards were often had peep refractory hypoxemia . it was also noted that once patients improved and the weaning process was started , oxygenation was sensitive to small decrements in peep .
use of noninvasive mechanical ventilation has some significant problems when there is risk of transmitting infectious diseases .
use of noninvasive ventilation was identified as risk factor for transmitting infection due to exposure to aerosols during sars epidemics 25 .
these were expert opinions but in an experimental model , it was claimed that noninvasive ventilatory support may increase occupational risk 26 .
however it was shown multiple times that noninvasive ventilatory support may decrease mortality with avoiding from endotracheal intubation .
it is difficult to identify immediately if patients are infected or not during epidemic so noninvasive ventilation can be initial chose of ventilatory support in those patients .
there is always a potential harm from a withholding a procedure while there is epidemics .
even if there is risk to use noninvasive ventilation for h1n1 patients since it may save the lives , we decided to use it under strict isolation including negative pressure isolation rooms . in conclusion , we have demonstrated that 2009 influenza a ( h1n1 ) infection - related critical illness predominantly affects young patients with little major comorbidity and is associated with severe hypoxemic respiratory failure , often requiring prolonged mechanical ventilation . among patients admitted to icu , older age , and a requirement for invasive ventilation
were associated with increased risk of death , but because there were greater numbers of younger patients in our cohort , the majority of deaths occurred in younger patients .
alternatively , nimv could be used in 2009 influenza a ( h1n1 ) infection - related hypoxemic respiratory failure .
 aim : we describe futures of icu admission , demographic characteristics , treatment and outcome for critically ill patients with laboratory - confirmed and suspected infection with the h1n1 virus admitted to the three different critical care departments in turkey.methods : retrospective study of critically ill patients with 2009 influenza a(h1n1 ) at icu . 
 demographic data , symptoms , comorbid conditions , and clinical outcomes were collected using a case report form.results : critical illness occurred in 61 patients admitted to an icu with confirmed ( n=45 ) or probable and suspected 2009 influenza a(h1n1 ) . 
 patients were young ( mean , 41.5 years ) , were female ( 54% ) . 
 fifty - six patients , required mechanical ventilation ( 14 invasive , 27 noninvasive , 15 both ) during the course of icu . on admission , 
 mean apache ii score was 18.76.3 and median pao2/fio2 was 127.970.4 . 
 31 patients ( 50.8% ) was die . 
 there were no significant differences in baseline pao2/fio2 and ventilation strategies between survivors and nonsurvivors . 
 patients who survived were more likely to have nimv use at the time of admission to the icu.conclusion : critical illness from 2009 influenza a(h1n1 ) in icu predominantly affects young patients with little major comorbidity and had a high case - fatality rate . 
 nimv could be used in 2009 influenza a ( h1n1 ) infection - related hypoxemic respiratory failure . 