- Email: [email protected]
Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock
+Model YICCN-2386; No. of Pages 7
ARTICLE IN PRESS
Intensive and Critical Care Nursing (2015) xxx, xxx—xxx
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/iccn
ORIGINAL ARTICLE
Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock夽 Wai Keung Cheung a,∗, Lai Sheung Chau b,1, Iun Ieng Laurinda Mak b,1, Mei Yi Wong b,1, Sai Leung Wong b,1, Agnes Fung Yee Tiwari a,2 a b
School of Nursing, The University of Hong Kong, Hong Kong Special Administrative Region Intensive Care Unit, Tuen Mun Hospital, Hong Kong Special Administrative Region
Accepted 24 April 2015
KEYWORDS Critical care nursing; Norepinephrine; Septic shock; Severe sepsis
Summary Background: The Surviving Sepsis Campaign promotes the use of norepinephrine as the first-line inotropic support for patients presenting with severe sepsis or septic shock in cases of persistent hypotension, despite adequate fluid resuscitation. However, there is little published evidence on how much noradrenaline is administered to such patients when admitted to the intensive care unit (ICU). The authors report the clinical management of this group of patients, with a special focus on the total amount and duration of norepinephrine infusion required. Methods: A chart review of the admission records of an ICU in Hong Kong was carried out in 2013. A total of 5000 patients were screened by their diagnosis of severe sepsis or septic shock (in the admissions book) between 1 January 2011 and 31 December 2013. A total of 150 of these were identified and 100 included in the study after simultaneous in-depth reviews of their case notes by two of the investigators. The analysis covers those with severe sepsis or septic shock who required ICU admission for further care. Clinical management and outcomes were analysed. Results: 100 patients (median age 61.6; M/F ratio 2:1) met the inclusion criteria. The mean ICU stay was 13.4 days (range = 1—371). 14 patients (14%) died in the ICU, with a 28-day mortality rate of 22%. The mean period of mechanical ventilation was 6.1 days (range = 0—137). 91.5% (n = 43) of patients had been operated on immediately before admission to the ICU, and the majority of these operations had been of the emergency type (97.7%, n = 43). The mean total volumes of crystalloid and colloid administered were 3420 ml and 478 ml, respectively. The mean wean-off period for norepinephrine infusion was 4234 minutes (70.5 hours). All patients were
夽
This study was performed in Intensive Care Unit of Tuen Mun Hospital, 23 Tsing Chung Koon Road, Tuen Mun, Hong Kong: SAR. Corresponding author. Tel.: +852 39176644. E-mail addresses: [email protected] (W.K. Cheung), [email protected] (L.S. Chau), [email protected] (I.I.L. Mak), [email protected] (M.Y. Wong), [email protected] (S.L. Wong), [email protected] (A.F.Y. Tiwari). 1 Tel.: +852 24637939. 2 Tel.: +852 28192633. ∗
http://dx.doi.org/10.1016/j.iccn.2015.04.005 0964-3397/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
+Model
ARTICLE IN PRESS
YICCN-2386; No. of Pages 7
2
W.K. Cheung et al. prescribed norepinephrine for persistent hypotension despite adequate fluid resuscitation, and the mean total amount administered was 87,211 mg. Final multiple linear and logistic regression analysis showed different clinical outcomes associated with different covariates, which included: (1) total amount of crystalloid given, positively associated with the total amount and duration of norepinephrine infusion; (2) duration of mechanical ventilation, positively associated with the type of operation the patient had undergone; (3) 28-day mortality rate, positively associated with the INR. Conclusions: What this study adds to knowledge about patients suffering from severe sepsis or septic shock: (1) the mean duration of norepinephrine infusion for septic shock patients in an ICU is almost three days; (2) the more crystalloid is required to correct hypoperfusion, the higher the dosage and longer the duration of norepinephrine infusion will be necessary; (3) the longer the patient’s INR, the higher the chances of death within 28 days. Since not all patients have their body weight measured on or after admission to the ICU, we suggest further research into indirect estimation of body weight by other means, such as anthropometric measures, to guide the use of drugs and nutritional support in the ICU. In addition, APACHE scores should be included in further studies to compare the severity of the patient’s condition in other research. Furthermore, since this study does not cover university hospital ICUs, we suggest that further research concerning such patients should compare and reflect similarities and differences between public and university hospitals in the territory. © 2015 Elsevier Ltd. All rights reserved.
Implications for Clinical Practice What is already known about the topic? • Protocolised resuscitation of patients with sepsis should be initiated once hypoperfusion is recognised and the patient requires critical care support. • Norepinephrine is the initial vasopressor of choice to maintain blood pressure for septic shock patient. What this paper adds • The mean duration of norepinephrine infusion for septic shock patients in an ICU is almost three days; • The more crystalloid that is required to correct hypoperfusion, the higher the dosage and longer the duration of norepinephrine infusion will be necessary; • The longer the patient’s INR, the higher the chances of death within 28 days.
Introduction Sepsis is the clinical syndrome that results from a dysregulated inflammatory response to an infection. It exists if two or more of the following abnormalities are present, along with either a culture-proven or a visually identified infection: • • • •
temperature >38.3 or <36 ◦ C heart rate >90 beats/minutes respiratory rate >20 breaths/minutes or PaCO2 <32 mmHg WBC >12000 cells/mm3 , <4000 cells/mm3 or >10% immature (band) forms.
Severe sepsis refers to sepsis plus at least one of the following signs of hypoperfusion or organ dysfunction: • areas of mottled skin • capillary refilling requiring three seconds or longer • urine output <0.5 ml/kg over at least one hour, or renal replacement therapy
• • • • • •
lactate >2 mmol/L abrupt change in mental status abnormal electro-encephalographic (EEG) findings platelet count <100,000 per ml disseminated intravascular coagulation acute lung injury or acute respiratory distress syndrome (ARDS) • cardiac dysfunction (i.e., left ventricular systolic dysfunction), as defined by echo-cardiography or direct measurement of the cardiac index.
Septic shock exists if there is severe sepsis, plus one or both of the following: • systematic mean blood pressure <60 mmHg (or <80 mmHg if the patient has baseline hypertension) despite adequate fluid resuscitation • maintaining systematic mean blood pressure at >60 mmHg (or >80 mmHg if the patient has baseline hypertension) requires dopamine >5 mcg/kg per minutes, norepinephrine >0.25 mcg/kg per minutes, or epinephrine
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
+Model YICCN-2386; No. of Pages 7
ARTICLE IN PRESS
Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock >0.25 mcg/kg per minutes, despite adequate fluid resuscitation (Neviere, 2013b). Many septic shock or severe sepsis patients require immediate critical care support. According to the Surviving Sepsis Campaign guidelines 2012 (Dellinger et al., 2013a), protocolised resuscitation of a patient with sepsis should be initiated once hypoperfusion is recognised, with the goal of keeping central venous pressure (CVP) 8—12 mmHg, mean arterial pressure (MAP) > 65 mmHg, urine output >0.5 ml/kg/hour and central venous or mixed venous oxygen saturation (Svo2 ) > 65% (Casserly et al., 2012). For haemodynamic support, norepinephrine or dopamine centrally administered are the initial vasopressors of choice to maintain MAP > 65 mmHg (Beale et al., 2004; Dellinger et al., 2004, 2008). All these targets require support in the critical-care unit. However, despite such support, the presence of septic shock or severe sepsis is still associated with high mortality, in both developed and developing countries (Beovic et al., 2008; Cheng et al., 2007; Elias et al., 2012; Jaramillo-Bustamante et al., 2012; Khan et al., 2012; Moore et al., 2011; Pociello Alminana et al., 2007; Suka et al., 2006; Vincent and Atalan, 2008; Wang et al., 2006). To treat patients with severe sepsis and septic shock, norepinephrine is now the first choice of many clinicians. A recent systematic review of randomised clinical trials showed the superiority of norepinephrine over dopamine for in-hospital or 28-day mortality with pooled RR: 0.91 (C.I. 0.83—0.99; p-value = 0.028) (Vasu et al., 2012), and many other studies also have similar findings (De Backer et al., 2012; Ferguson-Myrthil, 2012; Lamontagne et al., 2011; Sandifer and Jones, 2012). However, norepinephrine, like any other drug, may have considerable side effects, such as vasoconstriction in many vascular beds, decreased renal and visceral blood flow and impaired visceral organ function (Bellomo, 2003). The consequences of these side effects include gangrene of the extremities, where amputation may be required. Hence, norepinephrine should be phased out as soon as possible once the condition has stabilised. This study aims to explore (1) the clinical management of patients with septic shock or severe sepsis in a critical care unit, with a special focus on the total volume and amount of crystalloids and norepinephrine administered and (2) factors affecting the outcomes of this group of patients. Approval has been obtained from the ethics committees of both the hospital and the University.
Methods A chart review of ICU admission records was carried out in 2013, at a 26-bed unit spread over two wards on the same floor, a general ICU catering for both medical and surgical cases, including trauma, orthopaedic and neurosurgical patients. The annual turnover of patients is 1800—2000, making it one of the biggest ICUs in Hong Kong. The data collection period ran from 1 January 2011 to 31 December 2013, with patients admitted to the hospital’s ICU identified from the unit’s admission book. Admissions of all kinds within this period totalled 5000. Of the corresponding 5000 sets of records in the admission book, 150 showed an admission diagnosis of sepsis, septic shock or
3
severe sepsis. All 150 sets of case notes were reviewed by the principal investigators and the unit’s nurse consultant simultaneously, to determine whether patients fulfilled the inclusion or exclusion criteria, as follows. Inclusion criteria: requiring norepinephrine infusion as 1. Patients haemodynamic support after admission to ICU with a diagnosis of severe sepsis or septic shock; 2. Patients fulfilling the definition of sepsis, severe sepsis or septic shock (Neviere, 2013b) Exclusion criteria: 1. Aged under 18; 2. Pregnant; 3. Active bleeding, such as trauma, requiring more time to be stabilised by inotropic and blood transfusion; 4. Acute sudden deterioration, such as sudden acute stroke, requiring more time to be stabilised; 5. Death within 24 hours of admission to the ICU. Both investigators have over 13 years of critical care nursing experience, with postgraduate training in ICU work. 50 records were excluded because they did not fulfil the inclusion criteria or fulfilled the exclusion criteria. This process identified, by hand search, 100 patients requiring in-depth case note review. Data were then collected on a variety of baseline measures, such as demographics, history and laboratory test results. In addition, clinical management data were also collected for analysis, such as the total volume of crystalloid and colloid given, total amount and duration of norepinephrine given, duration of mechanical ventilation, length of ICU stay, 28-day mortality and details of any operation. Data analysis included descriptive statistics of different variables (proportion, mean, median, IQR, range and SD) depicting the distribution of these variables. In inferential statistics, simple linear and logistic regression was performed to detect any factors associated with 28-day mortality, duration and amount of norepinephrine infusion, and duration of mechanical ventilation. In order to avoid missing any possible factors, those covariates with p-values less than or equal to 0.1 were entered into the multiple linear or logistic regression models. Since the use of a higher level of significance (such as p-values <0.05) has the disadvantage of excluding variables that are of questionable importance at the model-building stage, the investigators critically reviewed all variables added into a model before reaching a decision on the final model. Stepwise regression would then be employed to screen out inappropriate factors. All analysis was performed by means of SPSS v20.0.
Results Patient characteristics The median age of patients was 61.6 (range 18—94) and the male-to-female ratio was 66:34 (approximately 2:1).
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
+Model
ARTICLE IN PRESS
YICCN-2386; No. of Pages 7
4
W.K. Cheung et al. Table 1 Patients’ physical and laboratory parameters during severe sepsis or septic shock with norepinephrine infusion in progress. Physiological parameter Maximum temperature during stay in ICU Heart rate on admission to ICU Maximum heart rate during stay in ICU Maximum troponin I during stay in ICU Minimum platelet count during stay in ICU Maximum INR during stay in ICU Maximum APTT during stay in ICU Maximum PT during stay in ICU Maximum white blood cell count during stay in ICU
Mean
SD ◦
38.4 ( C)
1.07
114 (bpm)
21.3
129 (bpm)
21.09
1.575 (g/L)
3.44
138.6 × 109 (platelets/L) 1.62
100.2 × 109 (platelets/L) 0.58
48.46 (secs)
17.57
18.46 (secs)
7.07
20.15 (cells/mm3)
9.65
would start once the patient was assessed on the basis of the physician’s clinical judgement. Either he decreased the dosage of norepinephrine infusion during his daily rounds, or the nurse started to titrate the norepinephrine infusion at 0.5—1 ml every hour to keep MAP > 65 mmHg or SBP > 110 mmHg if the physician had so prescribed during his rounds. Among 100 subjects, two had the weaning process interrupted by sudden cardiac arrest.
Factors associated with the duration of noradrenaline weaning Bivariate correlation and linear and logistic regression were performed to analyse any factor associated with the amount and duration of norepinephrine infusion, and other clinical outcomes such as duration of mechanical ventilation and 28-day mortality (Table 2).
Discussion
Admission, mortality and duration of stay in ICU The mean stay in the ICU was 13.4 days (range = 1—371). 14 patients (14%) died there, and the 28-day mortality rate was 22%. The mean duration of mechanical ventilation was 6.1 days (range = 0—137).
Details of operations Before or during their stay in the ICU, 47 patients underwent an operation. Of these, 43 (91.5%) had an operation immediately before admission, with the remaining four (8.5%) having a percutaneous tracheostomy during their stay in the unit, performed by the ICU physician. Most of these operations were of the emergency type (97.7%), with a mean duration of 103 minutes (SD = 106). The types of operation included: urological (2.3%), general abdominal (81.4%), orthopaedic (14%) and cardio-thoracic surgery (2.3%).
Physiological parameters Table 1 summarises physiological and laboratory parameters.
Fluid resuscitation According to the case notes review, once a patient was diagnosed with severe sepsis or septic shock and admitted to ICU, the mean total volume of crystalloid and colloid administered from ICU admission to cessation of norepinephrine infusion was 3420 ml and 478 ml, respectively, and that of noradrenaline was 87,211 mg (SD = 146,792 mg). The mean period needed for weaning the patient off noradrenaline infusion was 4234 minutes (SD = 4390 minutes). The weaning
This study describes the clinical management outcomes of patients in Hong Kong with severe sepsis or septic shock requiring admission to the ICU, giving local and international healthcare professionals a clearer view of the situation in the territory. The median age of patients in our study was 61.6, with a distribution skewed towards the left, meaning a large proportion of patients aged over 60. This is consistent with other studies related to patients with severe sepsis or septic shock requiring ICU care (Merouani et al., 2008; Miller et al., 2013) or emergency department admission (Gray et al., 2013; Tsapenko et al., 2013; Whittaker et al., 2013). The male-to-female ratio of patients was 2:1, slightly different from other studies, where the ratio is usually 1:1 (Gray et al., 2013; Hodgin and Moss, 2008; Merouani et al., 2008; Miller et al., 2013). One reason for this discrepancy may be the sample size, with only 100 patients (less than 2% of the total ICU admissions during the three-year study period) fulfilling the study criteria, while the sample size in other studies is usually very large (Gray et al., 2013; Miller et al., 2013). The reason may be related to the way the subjects were recruited, purely by ICU admission diagnosis, while many other studies use different methods to recruit subjects, such as finding the discharge diagnosis by means of hospital electronic records. Within the study period, 14% of the patients died in the ICU and the 28-day mortality rate was 22%, lower ICU mortality (Hernandez et al., 2006; Phua et al., 2011) than in other studies but similar 28-day mortality rates (Whittaker et al., 2013). The lower mortality rate and differences in the male-to-female ratio may be due to methodological issues. For instance, a recent study related to the management of severe sepsis in patients admitted to Asian intensive care units showed a hospital mortality rate of 44.5% (Phua et al., 2011). For patients with severe sepsis or septic shock, adequate fluid resuscitation with 20—30 ml/kg of starch or 40—60 ml/kg of saline should be administered to maintain a measured MAP > 65 mmHg or SBP > 110 mmHg (Neviere, 2013b). In our study, once a patient was admitted to the ICU with a diagnosis of severe sepsis or septic shock, the mean volume of crystalloid and colloid administered was 3420 ml
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
+Model YICCN-2386; No. of Pages 7
ARTICLE IN PRESS
Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock Table 2
5
Multi-variable analyses of different clinical outcomes with different factors.
Outcomes
Factor during ICU stay
p-Value
Final multi-variable model p-value
Total amount of norepinephrine given (mg)
Max body temperature (◦ C) Max APTT values (seconds) Max WBC count (cells/mm3 ) Duration of mechanical ventilation (days) Total amount of crystalloid given (ml)
0.044 0.033 0.048 0.078 0.0001
0.047 0.001 Excluded Excluded <0.0001
Duration of norepinephrine infusion (minutes)
Max body temperature (◦ C) Max APTT (seconds) Max WBC count (cells/mm3 ) Total amount of crystalloid given (ml) Epinephrine given before start of nonepinephrine (yes/no)
0.044 0.033 0.048 0.0001 0.0001
Excluded 0.007 Excluded <0.0001 0.017
Duration of mechanical ventilation (days)
Min platelet count (×109 platelets/L) Duration of norepinephrine infusion (minutes) Total amount of norepinephrine given (mg) Total amount of crystalloid given (ml) Type of operation (emergency/elective) OT magnitude (ultra major, major, minor)
0.075 0.016 0.078 0.056 0.0001 0.067
Excluded Excluded Excluded Excluded <0.0001 Excluded
28-Day mortality
Max body temperature (◦ C) Max INR Max APTT (seconds) Max PT (seconds) Epinephrine given before start of nonepinephrine (yes/no) Duration of norepinephrine infusion (minutes) Total amount of norepinephrine given (mg)
0.087 0.0001 0.001 0.0001 0.043 0.091 0.017
Excluded 0.029 Excluded Excluded Excluded Excluded Excluded
and 478 ml, respectively. However, only five of our 100 subjects were found to have had their body weight measured in the general ward, with no such measurement being taken on or after their admission to the ICU. For this reason, we did not know whether patients had had adequate fluid resuscitation or not, especially during the first six-hour resuscitation period. To make a comparison with standard guidelines, if we take 60 kg as an average body weight for our subjects, the mean volume of crystalloid administered was 57 ml/kg, which is consistent with the recommendation to achieve a minimum of 30 ml/kg of crystalloids in patients with sepsisinduced tissue hypoperfusion coupled with a suspicion of hypovolemia (Dellinger et al., 2013b). As a form of fluid therapy, 97% of patients were given crystalloids as the initial fluid of choice for resuscitation in cases of severe sepsis and septic shock, which is consistent with international guidelines for the management of such conditions (Dellinger et al., 2013a) that advise crystalloids as the initial fluid choice for resuscitation. As regards the choice of vasopressors, 100% of septic shock patients were prescribed norepinephrine in cases of persistent hypotension despite adequate fluid resuscitation, which is again consistent with the recommendations of international guidelines (Dellinger et al., 2013a). The total amount of norepinephrine administered after diagnosis with severe sepsis or septic shock was 87,211 mg. Again, since we did not know the actual body weight of the patient on or after admission to the ICU, we could not compare the mean total amount with that appearing in other
international guidelines or studies, as most of these calculate the amount in g/kg per minutes. This reflects a common practice in Hong Kong ICUs, prescribing inotropics in millilitres per hour (ml/hr) without clearly stating what the patient’s body weight is estimated to be. High-dose norepinephrine infusion has many side effects (Bellomo, 2003), but it is required to sustain life and maintain perfusion in the face of life-threatening hypotension, even when hypovolemia has not yet been resolved (Dellinger et al., 2013a). Efforts should be directed to weaning patients off such treatment by continuing fluid resuscitation to correct the underlying problem of hypovolemia, as long as there is haemodynamic improvement based either on dynamic (e.g. change in pulse pressure, stroke volume variation) or on static (e.g. arterial pressure, heart rate) variables (Dellinger et al., 2013a). In the present study, we calculated the duration of norepinephrine infusion in the ICU and found it to be 4234 minutes (70.5 hours). Very few studies mention the duration of norepinephrine infusion for such patients, and indeed we found only one, carried out in France in 2008, that used a computer-controlled syringe to titrate norepinephrine, based on a protocol, with a mean duration of 57.5 hours in the control group (Merouani et al., 2008). However, our study took place in a general public hospital while the French site was a university hospital. The type of patients and the severity of their condition, manpower levels and admission criteria may all be different, and we assume the admission criteria for a university hospital’s ICU are more stringent and its manpower more generous than
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
+Model YICCN-2386; No. of Pages 7
ARTICLE IN PRESS
6
W.K. Cheung et al.
those of a general public hospital’s ICU in Hong Kong. This may account for the longer period of norepinephrine infusion weaning in Hong Kong. The final multiple linear or logistic regression analysis shows different clinical outcomes associated with different covariates. The total amount of crystalloid given to the patient has a positive association with the total amount and duration of norepinephrine administered (p-value <0.0001). Once a patient is diagnosed with severe sepsis or septic shock, for every 1 ml increase in the total amount of crystalloid administered there will be a 0.25 mg increase in the total amount of norepinephrine subsequently required to manage the condition in case of persistent hypotension, despite adequate fluid resuscitation being given. Also, for every 1 ml increase in the total amount of crystalloid given to the patient, there will be a one-minute increase in the subsequent duration of norepinephrine treatment. However, this does not mean that the total amount of crystalloid administered during the resuscitation period should be limited in the expectation that there will be a subsequent reduction in the total amount and duration of norepinephrine infusion. Hypotension in severe sepsis and septic shock is probably an unintended consequence of the release of vasoactive mediators that cause severe vasodilation within the body, and the result of redistribution of intravascular fluid due to both increased endothelial permeability and reduced arterial vascular tone, leading to increased capillary pressure (Neviere, 2013a). This positive association between the total amount of crystalloid and the subsequent duration and amount of norepinephrine administered should be interpreted according to the severity of the patient’s condition. If more crystalloid is required to correct the hypoperfusion, a higher dosage and longer duration of norepinephrine infusion will be required subsequently because of the severity of the condition. Further research is suggested to explore the possibilities of using the total volume of crystalloid infused as a predictive indicator of the duration and total amount of norepinephrine infusion required for a patient with severe sepsis or septic shock. Another interesting finding of this study is the relationship between the type of operation the patient undergoes and the subsequent duration of mechanical ventilation. About half (47%) of the subjects were operated on immediately before being admitted to the ICU, and most operations were of the emergency type (89.4%). We found the subsequent post-operative duration of mechanical ventilation to be longer when an emergency operation was performed immediately before admission to the ICU (p < 0.0001). However, although patients requiring emergency operations may be in poorer condition, it is impossible to be sure of the facts, since APACHE scores were not calculated in this study and hence no comparison can be made among patients with illnesses of different severity. The final multiple logistic regression model dealing with the relationship between the 28-day mortality rate and other correlated covariates showed that the longer the INR of the patient, the higher the chance of death within 28 days (p = 0.029). This relationship strongly suggests that the INR should be controlled within a normal range in order to lower the 28-day rate but, according to the international guidelines (Dellinger et al., 2013a), no studies suggest the use of fresh frozen plasma to correct laboratory clotting
abnormalities for patients who are not bleeding. We may need further research to clarify the relationship between prolonged INR and 28-day mortality.
Limitations of the study As mentioned in the discussion section above, the sample size and the estimation of ICU mortality were limited by the methods we used to recruit subjects. Recruitment was simply by way of the ICU admission diagnosis, and then a case record review to exclude those either not fitting the inclusion criteria or fulfilling the exclusion criteria, while many other studies have used different methods to recruit their subjects, such as searching the hospital electronic records of discharge diagnoses. Patients diagnosed with severe sepsis or septic shock after their admission to ICU will therefore be missed in this study, which may be one reason for such a low ICU mortality rate when compared with other studies. Hence, the low rate may not reflect the true situation and further research into the issue is clearly required. Additionally, the amount of crystalloid and norepinephrine administered per kilogram per minute was limited by the lack of any body weight measurement in the ICU, and hence restricts any comparison between local and international studies, and all international guidelines. Another limitation is the severity of the patient’s condition. The type of patients in the study may have been in poorer condition and hence required ICU admission. This may have affected the total volume and amount of crystalloids and norepinephrine infusion plus the duration of mechanical ventilation. However, it is not possible to know for certain, since APACHE scores were not calculated in this study, and so a comparison of its results with those of other local or international studies is not possible as far as the severity of the patients’ condition is concerned.
Conclusion In summary, we hope this study may provide local and international healthcare workers with more information about the clinical management of ICU patients in Hong Kong suffering from severe sepsis or septic shock, and about their subsequent clinical outcomes. What this study adds to the present body of knowledge about such patients includes: (1) the mean duration of norepinephrine infusion in ICU for septic shock patients is almost three days; (2) the more crystalloid is required to correct the hypoperfusion, the higher dosage and longer duration of norepinephrine infusion will be required; (3) the longer the patient’s INR, the higher the chance of death within 28 days. Since no patients had their body weight measured on or after admission to the ICU, we suggest further research on any indirect estimation of body weight by other means, such as anthropometrics measures, to guide the use of drugs and nutritional support in the ICU. In addition, APACHE scores should be calculated in any further study, in order to compare the severity of the patients’ condition with that in other studies. Furthermore, since this study does not cover any university hospital ICU, we suggest that further research on such patients should compare and reflect similarities and differences between public and university hospitals in the territory.
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
+Model YICCN-2386; No. of Pages 7
ARTICLE IN PRESS
Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock
Funding The authors have no sources of funding to declare.
Conflict of interest The authors have no conflict of interest to declare.
References Beale RJ, Hollenberg SM, Vincent JL, Parrillo JE. Vasopressor and inotropic support in septic shock: an evidence-based review. Crit Care Med 2004;32:S455—65. Bellomo R. Noradrenaline: friend or foe? Heart Lung Circ 2003;12(Suppl. 2):S42—8. Beovic B, Hladnik Z, Pozenel P, Siuka D, Slovenian Severe Sepsis Study G. Epidemiology of severe sepsis in Slovenian intensive care units for adults. J Chemother 2008;20:134—6. Casserly B, Gerlach H, Phillips GS, Lemeshow S, Marshall JC, Osborn TM, et al. Low-dose steroids in adult septic shock: results of the Surviving Sepsis Campaign. Intensive Care Med 2012;38:1946—54. Cheng B, Xie G, Yao S, Wu X, Guo Q, Gu M, et al. Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Crit Care Med 2007;35:2538—46. De Backer D, Aldecoa C, Njimi H, Vincent JL. Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis*. Crit Care Med 2012;40:725—30. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32: 858—73. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 2008;34:17—60. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Intensive Care Med 2013a;39:165—228. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013b;41:580—637. Elias AC, Matsuo T, Grion CM, Cardoso LT, Verri PH. Incidence and risk factors for sepsis in surgical patients: a cohort study. J Crit Care 2012;27:159—66. Ferguson-Myrthil N. Vasopressor use in adult patients. Cardiol Rev 2012;20:153—8. Gray A, Ward K, Lees F, Dewar C, Dickie S, McGuffie C, et al. The epidemiology of adults with severe sepsis and septic shock in Scottish emergency departments. Emerg Med J 2013;30:397—401. Hernandez G, Bruhn A, Romero C, Larrondo FJ, De La Fuente R, Cornejo R, et al. Implementation of a norepinephrine-based
7
protocol for management of septic shock: a pilot feasibility study. J Trauma 2006;60:77—81. Hodgin KE, Moss M. The epidemiology of sepsis. Curr Pharm Des 2008;14:1833—9. Jaramillo-Bustamante JC, Marin-Agudelo A, Fernandez-Laverde M, Bareno-Silva J. Epidemiology of sepsis in pediatric intensive care units: First Colombian Multicenter Study. Pediatr Crit Care Med 2012;13(5):501—8. Khan MR, Maheshwari PK, Masood K, Qamar FN, Haque AU. Epidemiology and outcome of sepsis in a tertiary care PICU of Pakistan. Indian J Pediatr 2012;79(11):1454—8. Lamontagne F, Cook DJ, Adhikari NK, Briel M, Duffett M, Kho ME, et al. Vasopressor administration and sepsis: a survey of Canadian intensivists. J Crit Care 2011;26:532 e1—e5327. Merouani M, Guignard B, Vincent F, Borron SW, Karoubi P, Fosse JP, et al. Norepinephrine weaning in septic shock patients by closed loop control based on fuzzy logic. Crit Care 2008;12:R155. Miller RR 3rd, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst DR, et al. Multicenter implementation of a severe sepsis and septic shock treatment bundle. Am J Respir Crit Care Med 2013;188:77—82. Moore LJ, McKinley BA, Turner KL, Todd SR, Sucher JF, Valdivia A, et al. The epidemiology of sepsis in general surgery patients. J Trauma 2011;70:672—80. Neviere R. Pathophysiology of sepsis; 2013a. Neviere R. Sepsis and the systematic inflammatory response syndrome: definitions, epidemiology, and prognosis; 2013b. Phua J, Koh Y, Du B, Tang Y-Q, Divatia JV, Tan CC, et al. Management of severe sepsis in patients admitted to Asian intensive care units: prospective cohort study. Brit Med J 2011;342:d3245. Pociello Alminana N, Balaguer Gargallo M, Jordan Garcia I, Corrales Magin E, Esteban Torne E, Munoz Almagro C, et al. Epidemiology and clinical findings in late-onset neonatal sepsis in the pediatric intensive care unit. An Pediatr (Barc) 2007;67:604—5. Sandifer JP, Jones AE. Dopamine versus norepinephrine for the treatment of septic shock EBEM commentators. Ann Emerg Med 2012;60(3):372—3. Suka M, Yoshida K, Takezawa J. Incidence and outcome of sepsis in Japanese intensive care units: the Japanese nosocomial infection surveillance system. Environ Health Prev Med 2006;11:298—303. Tsapenko MV, Herasevich V, Mour GK, Tsapenko AV, Comfere TB, Mankad SV, et al. Severe sepsis and septic shock in patients with pre-existing non-cardiac pulmonary hypertension: contemporary management and outcomes. Crit Care Resusc 2013;15:103—9. Vasu TS, Cavallazzi R, Hirani A, Kaplan G, Leiby B, Marik PE. Norepinephrine or dopamine for septic shock: systematic review of randomized clinical trials. J Intensive Care Med 2012;27:172—8. Vincent JL, Atalan HK. Epidemiology of severe sepsis in the intensive care unit. Br J Hosp Med (Lond) 2008;69:442—3. Wang M, Peng W, Cai M, Ji G. Investigation on epidemiology in 645 cases with sepsis in surgical intensive care unit. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2006;18:74—7. Whittaker SA, Mikkelsen ME, Gaieski DF, Koshy S, Kean C, Fuchs BD. Severe sepsis cohorts derived from claims-based strategies appear to be biased toward a more severely ill patient population. Crit Care Med 2013;41:945—53.
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
ARTICLE IN PRESS
Intensive and Critical Care Nursing (2015) xxx, xxx—xxx
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/iccn
ORIGINAL ARTICLE
Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock夽 Wai Keung Cheung a,∗, Lai Sheung Chau b,1, Iun Ieng Laurinda Mak b,1, Mei Yi Wong b,1, Sai Leung Wong b,1, Agnes Fung Yee Tiwari a,2 a b
School of Nursing, The University of Hong Kong, Hong Kong Special Administrative Region Intensive Care Unit, Tuen Mun Hospital, Hong Kong Special Administrative Region
Accepted 24 April 2015
KEYWORDS Critical care nursing; Norepinephrine; Septic shock; Severe sepsis
Summary Background: The Surviving Sepsis Campaign promotes the use of norepinephrine as the first-line inotropic support for patients presenting with severe sepsis or septic shock in cases of persistent hypotension, despite adequate fluid resuscitation. However, there is little published evidence on how much noradrenaline is administered to such patients when admitted to the intensive care unit (ICU). The authors report the clinical management of this group of patients, with a special focus on the total amount and duration of norepinephrine infusion required. Methods: A chart review of the admission records of an ICU in Hong Kong was carried out in 2013. A total of 5000 patients were screened by their diagnosis of severe sepsis or septic shock (in the admissions book) between 1 January 2011 and 31 December 2013. A total of 150 of these were identified and 100 included in the study after simultaneous in-depth reviews of their case notes by two of the investigators. The analysis covers those with severe sepsis or septic shock who required ICU admission for further care. Clinical management and outcomes were analysed. Results: 100 patients (median age 61.6; M/F ratio 2:1) met the inclusion criteria. The mean ICU stay was 13.4 days (range = 1—371). 14 patients (14%) died in the ICU, with a 28-day mortality rate of 22%. The mean period of mechanical ventilation was 6.1 days (range = 0—137). 91.5% (n = 43) of patients had been operated on immediately before admission to the ICU, and the majority of these operations had been of the emergency type (97.7%, n = 43). The mean total volumes of crystalloid and colloid administered were 3420 ml and 478 ml, respectively. The mean wean-off period for norepinephrine infusion was 4234 minutes (70.5 hours). All patients were
夽
This study was performed in Intensive Care Unit of Tuen Mun Hospital, 23 Tsing Chung Koon Road, Tuen Mun, Hong Kong: SAR. Corresponding author. Tel.: +852 39176644. E-mail addresses: [email protected] (W.K. Cheung), [email protected] (L.S. Chau), [email protected] (I.I.L. Mak), [email protected] (M.Y. Wong), [email protected] (S.L. Wong), [email protected] (A.F.Y. Tiwari). 1 Tel.: +852 24637939. 2 Tel.: +852 28192633. ∗
http://dx.doi.org/10.1016/j.iccn.2015.04.005 0964-3397/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
+Model
ARTICLE IN PRESS
YICCN-2386; No. of Pages 7
2
W.K. Cheung et al. prescribed norepinephrine for persistent hypotension despite adequate fluid resuscitation, and the mean total amount administered was 87,211 mg. Final multiple linear and logistic regression analysis showed different clinical outcomes associated with different covariates, which included: (1) total amount of crystalloid given, positively associated with the total amount and duration of norepinephrine infusion; (2) duration of mechanical ventilation, positively associated with the type of operation the patient had undergone; (3) 28-day mortality rate, positively associated with the INR. Conclusions: What this study adds to knowledge about patients suffering from severe sepsis or septic shock: (1) the mean duration of norepinephrine infusion for septic shock patients in an ICU is almost three days; (2) the more crystalloid is required to correct hypoperfusion, the higher the dosage and longer the duration of norepinephrine infusion will be necessary; (3) the longer the patient’s INR, the higher the chances of death within 28 days. Since not all patients have their body weight measured on or after admission to the ICU, we suggest further research into indirect estimation of body weight by other means, such as anthropometric measures, to guide the use of drugs and nutritional support in the ICU. In addition, APACHE scores should be included in further studies to compare the severity of the patient’s condition in other research. Furthermore, since this study does not cover university hospital ICUs, we suggest that further research concerning such patients should compare and reflect similarities and differences between public and university hospitals in the territory. © 2015 Elsevier Ltd. All rights reserved.
Implications for Clinical Practice What is already known about the topic? • Protocolised resuscitation of patients with sepsis should be initiated once hypoperfusion is recognised and the patient requires critical care support. • Norepinephrine is the initial vasopressor of choice to maintain blood pressure for septic shock patient. What this paper adds • The mean duration of norepinephrine infusion for septic shock patients in an ICU is almost three days; • The more crystalloid that is required to correct hypoperfusion, the higher the dosage and longer the duration of norepinephrine infusion will be necessary; • The longer the patient’s INR, the higher the chances of death within 28 days.
Introduction Sepsis is the clinical syndrome that results from a dysregulated inflammatory response to an infection. It exists if two or more of the following abnormalities are present, along with either a culture-proven or a visually identified infection: • • • •
temperature >38.3 or <36 ◦ C heart rate >90 beats/minutes respiratory rate >20 breaths/minutes or PaCO2 <32 mmHg WBC >12000 cells/mm3 , <4000 cells/mm3 or >10% immature (band) forms.
Severe sepsis refers to sepsis plus at least one of the following signs of hypoperfusion or organ dysfunction: • areas of mottled skin • capillary refilling requiring three seconds or longer • urine output <0.5 ml/kg over at least one hour, or renal replacement therapy
• • • • • •
lactate >2 mmol/L abrupt change in mental status abnormal electro-encephalographic (EEG) findings platelet count <100,000 per ml disseminated intravascular coagulation acute lung injury or acute respiratory distress syndrome (ARDS) • cardiac dysfunction (i.e., left ventricular systolic dysfunction), as defined by echo-cardiography or direct measurement of the cardiac index.
Septic shock exists if there is severe sepsis, plus one or both of the following: • systematic mean blood pressure <60 mmHg (or <80 mmHg if the patient has baseline hypertension) despite adequate fluid resuscitation • maintaining systematic mean blood pressure at >60 mmHg (or >80 mmHg if the patient has baseline hypertension) requires dopamine >5 mcg/kg per minutes, norepinephrine >0.25 mcg/kg per minutes, or epinephrine
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
+Model YICCN-2386; No. of Pages 7
ARTICLE IN PRESS
Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock >0.25 mcg/kg per minutes, despite adequate fluid resuscitation (Neviere, 2013b). Many septic shock or severe sepsis patients require immediate critical care support. According to the Surviving Sepsis Campaign guidelines 2012 (Dellinger et al., 2013a), protocolised resuscitation of a patient with sepsis should be initiated once hypoperfusion is recognised, with the goal of keeping central venous pressure (CVP) 8—12 mmHg, mean arterial pressure (MAP) > 65 mmHg, urine output >0.5 ml/kg/hour and central venous or mixed venous oxygen saturation (Svo2 ) > 65% (Casserly et al., 2012). For haemodynamic support, norepinephrine or dopamine centrally administered are the initial vasopressors of choice to maintain MAP > 65 mmHg (Beale et al., 2004; Dellinger et al., 2004, 2008). All these targets require support in the critical-care unit. However, despite such support, the presence of septic shock or severe sepsis is still associated with high mortality, in both developed and developing countries (Beovic et al., 2008; Cheng et al., 2007; Elias et al., 2012; Jaramillo-Bustamante et al., 2012; Khan et al., 2012; Moore et al., 2011; Pociello Alminana et al., 2007; Suka et al., 2006; Vincent and Atalan, 2008; Wang et al., 2006). To treat patients with severe sepsis and septic shock, norepinephrine is now the first choice of many clinicians. A recent systematic review of randomised clinical trials showed the superiority of norepinephrine over dopamine for in-hospital or 28-day mortality with pooled RR: 0.91 (C.I. 0.83—0.99; p-value = 0.028) (Vasu et al., 2012), and many other studies also have similar findings (De Backer et al., 2012; Ferguson-Myrthil, 2012; Lamontagne et al., 2011; Sandifer and Jones, 2012). However, norepinephrine, like any other drug, may have considerable side effects, such as vasoconstriction in many vascular beds, decreased renal and visceral blood flow and impaired visceral organ function (Bellomo, 2003). The consequences of these side effects include gangrene of the extremities, where amputation may be required. Hence, norepinephrine should be phased out as soon as possible once the condition has stabilised. This study aims to explore (1) the clinical management of patients with septic shock or severe sepsis in a critical care unit, with a special focus on the total volume and amount of crystalloids and norepinephrine administered and (2) factors affecting the outcomes of this group of patients. Approval has been obtained from the ethics committees of both the hospital and the University.
Methods A chart review of ICU admission records was carried out in 2013, at a 26-bed unit spread over two wards on the same floor, a general ICU catering for both medical and surgical cases, including trauma, orthopaedic and neurosurgical patients. The annual turnover of patients is 1800—2000, making it one of the biggest ICUs in Hong Kong. The data collection period ran from 1 January 2011 to 31 December 2013, with patients admitted to the hospital’s ICU identified from the unit’s admission book. Admissions of all kinds within this period totalled 5000. Of the corresponding 5000 sets of records in the admission book, 150 showed an admission diagnosis of sepsis, septic shock or
3
severe sepsis. All 150 sets of case notes were reviewed by the principal investigators and the unit’s nurse consultant simultaneously, to determine whether patients fulfilled the inclusion or exclusion criteria, as follows. Inclusion criteria: requiring norepinephrine infusion as 1. Patients haemodynamic support after admission to ICU with a diagnosis of severe sepsis or septic shock; 2. Patients fulfilling the definition of sepsis, severe sepsis or septic shock (Neviere, 2013b) Exclusion criteria: 1. Aged under 18; 2. Pregnant; 3. Active bleeding, such as trauma, requiring more time to be stabilised by inotropic and blood transfusion; 4. Acute sudden deterioration, such as sudden acute stroke, requiring more time to be stabilised; 5. Death within 24 hours of admission to the ICU. Both investigators have over 13 years of critical care nursing experience, with postgraduate training in ICU work. 50 records were excluded because they did not fulfil the inclusion criteria or fulfilled the exclusion criteria. This process identified, by hand search, 100 patients requiring in-depth case note review. Data were then collected on a variety of baseline measures, such as demographics, history and laboratory test results. In addition, clinical management data were also collected for analysis, such as the total volume of crystalloid and colloid given, total amount and duration of norepinephrine given, duration of mechanical ventilation, length of ICU stay, 28-day mortality and details of any operation. Data analysis included descriptive statistics of different variables (proportion, mean, median, IQR, range and SD) depicting the distribution of these variables. In inferential statistics, simple linear and logistic regression was performed to detect any factors associated with 28-day mortality, duration and amount of norepinephrine infusion, and duration of mechanical ventilation. In order to avoid missing any possible factors, those covariates with p-values less than or equal to 0.1 were entered into the multiple linear or logistic regression models. Since the use of a higher level of significance (such as p-values <0.05) has the disadvantage of excluding variables that are of questionable importance at the model-building stage, the investigators critically reviewed all variables added into a model before reaching a decision on the final model. Stepwise regression would then be employed to screen out inappropriate factors. All analysis was performed by means of SPSS v20.0.
Results Patient characteristics The median age of patients was 61.6 (range 18—94) and the male-to-female ratio was 66:34 (approximately 2:1).
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
+Model
ARTICLE IN PRESS
YICCN-2386; No. of Pages 7
4
W.K. Cheung et al. Table 1 Patients’ physical and laboratory parameters during severe sepsis or septic shock with norepinephrine infusion in progress. Physiological parameter Maximum temperature during stay in ICU Heart rate on admission to ICU Maximum heart rate during stay in ICU Maximum troponin I during stay in ICU Minimum platelet count during stay in ICU Maximum INR during stay in ICU Maximum APTT during stay in ICU Maximum PT during stay in ICU Maximum white blood cell count during stay in ICU
Mean
SD ◦
38.4 ( C)
1.07
114 (bpm)
21.3
129 (bpm)
21.09
1.575 (g/L)
3.44
138.6 × 109 (platelets/L) 1.62
100.2 × 109 (platelets/L) 0.58
48.46 (secs)
17.57
18.46 (secs)
7.07
20.15 (cells/mm3)
9.65
would start once the patient was assessed on the basis of the physician’s clinical judgement. Either he decreased the dosage of norepinephrine infusion during his daily rounds, or the nurse started to titrate the norepinephrine infusion at 0.5—1 ml every hour to keep MAP > 65 mmHg or SBP > 110 mmHg if the physician had so prescribed during his rounds. Among 100 subjects, two had the weaning process interrupted by sudden cardiac arrest.
Factors associated with the duration of noradrenaline weaning Bivariate correlation and linear and logistic regression were performed to analyse any factor associated with the amount and duration of norepinephrine infusion, and other clinical outcomes such as duration of mechanical ventilation and 28-day mortality (Table 2).
Discussion
Admission, mortality and duration of stay in ICU The mean stay in the ICU was 13.4 days (range = 1—371). 14 patients (14%) died there, and the 28-day mortality rate was 22%. The mean duration of mechanical ventilation was 6.1 days (range = 0—137).
Details of operations Before or during their stay in the ICU, 47 patients underwent an operation. Of these, 43 (91.5%) had an operation immediately before admission, with the remaining four (8.5%) having a percutaneous tracheostomy during their stay in the unit, performed by the ICU physician. Most of these operations were of the emergency type (97.7%), with a mean duration of 103 minutes (SD = 106). The types of operation included: urological (2.3%), general abdominal (81.4%), orthopaedic (14%) and cardio-thoracic surgery (2.3%).
Physiological parameters Table 1 summarises physiological and laboratory parameters.
Fluid resuscitation According to the case notes review, once a patient was diagnosed with severe sepsis or septic shock and admitted to ICU, the mean total volume of crystalloid and colloid administered from ICU admission to cessation of norepinephrine infusion was 3420 ml and 478 ml, respectively, and that of noradrenaline was 87,211 mg (SD = 146,792 mg). The mean period needed for weaning the patient off noradrenaline infusion was 4234 minutes (SD = 4390 minutes). The weaning
This study describes the clinical management outcomes of patients in Hong Kong with severe sepsis or septic shock requiring admission to the ICU, giving local and international healthcare professionals a clearer view of the situation in the territory. The median age of patients in our study was 61.6, with a distribution skewed towards the left, meaning a large proportion of patients aged over 60. This is consistent with other studies related to patients with severe sepsis or septic shock requiring ICU care (Merouani et al., 2008; Miller et al., 2013) or emergency department admission (Gray et al., 2013; Tsapenko et al., 2013; Whittaker et al., 2013). The male-to-female ratio of patients was 2:1, slightly different from other studies, where the ratio is usually 1:1 (Gray et al., 2013; Hodgin and Moss, 2008; Merouani et al., 2008; Miller et al., 2013). One reason for this discrepancy may be the sample size, with only 100 patients (less than 2% of the total ICU admissions during the three-year study period) fulfilling the study criteria, while the sample size in other studies is usually very large (Gray et al., 2013; Miller et al., 2013). The reason may be related to the way the subjects were recruited, purely by ICU admission diagnosis, while many other studies use different methods to recruit subjects, such as finding the discharge diagnosis by means of hospital electronic records. Within the study period, 14% of the patients died in the ICU and the 28-day mortality rate was 22%, lower ICU mortality (Hernandez et al., 2006; Phua et al., 2011) than in other studies but similar 28-day mortality rates (Whittaker et al., 2013). The lower mortality rate and differences in the male-to-female ratio may be due to methodological issues. For instance, a recent study related to the management of severe sepsis in patients admitted to Asian intensive care units showed a hospital mortality rate of 44.5% (Phua et al., 2011). For patients with severe sepsis or septic shock, adequate fluid resuscitation with 20—30 ml/kg of starch or 40—60 ml/kg of saline should be administered to maintain a measured MAP > 65 mmHg or SBP > 110 mmHg (Neviere, 2013b). In our study, once a patient was admitted to the ICU with a diagnosis of severe sepsis or septic shock, the mean volume of crystalloid and colloid administered was 3420 ml
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
+Model YICCN-2386; No. of Pages 7
ARTICLE IN PRESS
Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock Table 2
5
Multi-variable analyses of different clinical outcomes with different factors.
Outcomes
Factor during ICU stay
p-Value
Final multi-variable model p-value
Total amount of norepinephrine given (mg)
Max body temperature (◦ C) Max APTT values (seconds) Max WBC count (cells/mm3 ) Duration of mechanical ventilation (days) Total amount of crystalloid given (ml)
0.044 0.033 0.048 0.078 0.0001
0.047 0.001 Excluded Excluded <0.0001
Duration of norepinephrine infusion (minutes)
Max body temperature (◦ C) Max APTT (seconds) Max WBC count (cells/mm3 ) Total amount of crystalloid given (ml) Epinephrine given before start of nonepinephrine (yes/no)
0.044 0.033 0.048 0.0001 0.0001
Excluded 0.007 Excluded <0.0001 0.017
Duration of mechanical ventilation (days)
Min platelet count (×109 platelets/L) Duration of norepinephrine infusion (minutes) Total amount of norepinephrine given (mg) Total amount of crystalloid given (ml) Type of operation (emergency/elective) OT magnitude (ultra major, major, minor)
0.075 0.016 0.078 0.056 0.0001 0.067
Excluded Excluded Excluded Excluded <0.0001 Excluded
28-Day mortality
Max body temperature (◦ C) Max INR Max APTT (seconds) Max PT (seconds) Epinephrine given before start of nonepinephrine (yes/no) Duration of norepinephrine infusion (minutes) Total amount of norepinephrine given (mg)
0.087 0.0001 0.001 0.0001 0.043 0.091 0.017
Excluded 0.029 Excluded Excluded Excluded Excluded Excluded
and 478 ml, respectively. However, only five of our 100 subjects were found to have had their body weight measured in the general ward, with no such measurement being taken on or after their admission to the ICU. For this reason, we did not know whether patients had had adequate fluid resuscitation or not, especially during the first six-hour resuscitation period. To make a comparison with standard guidelines, if we take 60 kg as an average body weight for our subjects, the mean volume of crystalloid administered was 57 ml/kg, which is consistent with the recommendation to achieve a minimum of 30 ml/kg of crystalloids in patients with sepsisinduced tissue hypoperfusion coupled with a suspicion of hypovolemia (Dellinger et al., 2013b). As a form of fluid therapy, 97% of patients were given crystalloids as the initial fluid of choice for resuscitation in cases of severe sepsis and septic shock, which is consistent with international guidelines for the management of such conditions (Dellinger et al., 2013a) that advise crystalloids as the initial fluid choice for resuscitation. As regards the choice of vasopressors, 100% of septic shock patients were prescribed norepinephrine in cases of persistent hypotension despite adequate fluid resuscitation, which is again consistent with the recommendations of international guidelines (Dellinger et al., 2013a). The total amount of norepinephrine administered after diagnosis with severe sepsis or septic shock was 87,211 mg. Again, since we did not know the actual body weight of the patient on or after admission to the ICU, we could not compare the mean total amount with that appearing in other
international guidelines or studies, as most of these calculate the amount in g/kg per minutes. This reflects a common practice in Hong Kong ICUs, prescribing inotropics in millilitres per hour (ml/hr) without clearly stating what the patient’s body weight is estimated to be. High-dose norepinephrine infusion has many side effects (Bellomo, 2003), but it is required to sustain life and maintain perfusion in the face of life-threatening hypotension, even when hypovolemia has not yet been resolved (Dellinger et al., 2013a). Efforts should be directed to weaning patients off such treatment by continuing fluid resuscitation to correct the underlying problem of hypovolemia, as long as there is haemodynamic improvement based either on dynamic (e.g. change in pulse pressure, stroke volume variation) or on static (e.g. arterial pressure, heart rate) variables (Dellinger et al., 2013a). In the present study, we calculated the duration of norepinephrine infusion in the ICU and found it to be 4234 minutes (70.5 hours). Very few studies mention the duration of norepinephrine infusion for such patients, and indeed we found only one, carried out in France in 2008, that used a computer-controlled syringe to titrate norepinephrine, based on a protocol, with a mean duration of 57.5 hours in the control group (Merouani et al., 2008). However, our study took place in a general public hospital while the French site was a university hospital. The type of patients and the severity of their condition, manpower levels and admission criteria may all be different, and we assume the admission criteria for a university hospital’s ICU are more stringent and its manpower more generous than
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
+Model YICCN-2386; No. of Pages 7
ARTICLE IN PRESS
6
W.K. Cheung et al.
those of a general public hospital’s ICU in Hong Kong. This may account for the longer period of norepinephrine infusion weaning in Hong Kong. The final multiple linear or logistic regression analysis shows different clinical outcomes associated with different covariates. The total amount of crystalloid given to the patient has a positive association with the total amount and duration of norepinephrine administered (p-value <0.0001). Once a patient is diagnosed with severe sepsis or septic shock, for every 1 ml increase in the total amount of crystalloid administered there will be a 0.25 mg increase in the total amount of norepinephrine subsequently required to manage the condition in case of persistent hypotension, despite adequate fluid resuscitation being given. Also, for every 1 ml increase in the total amount of crystalloid given to the patient, there will be a one-minute increase in the subsequent duration of norepinephrine treatment. However, this does not mean that the total amount of crystalloid administered during the resuscitation period should be limited in the expectation that there will be a subsequent reduction in the total amount and duration of norepinephrine infusion. Hypotension in severe sepsis and septic shock is probably an unintended consequence of the release of vasoactive mediators that cause severe vasodilation within the body, and the result of redistribution of intravascular fluid due to both increased endothelial permeability and reduced arterial vascular tone, leading to increased capillary pressure (Neviere, 2013a). This positive association between the total amount of crystalloid and the subsequent duration and amount of norepinephrine administered should be interpreted according to the severity of the patient’s condition. If more crystalloid is required to correct the hypoperfusion, a higher dosage and longer duration of norepinephrine infusion will be required subsequently because of the severity of the condition. Further research is suggested to explore the possibilities of using the total volume of crystalloid infused as a predictive indicator of the duration and total amount of norepinephrine infusion required for a patient with severe sepsis or septic shock. Another interesting finding of this study is the relationship between the type of operation the patient undergoes and the subsequent duration of mechanical ventilation. About half (47%) of the subjects were operated on immediately before being admitted to the ICU, and most operations were of the emergency type (89.4%). We found the subsequent post-operative duration of mechanical ventilation to be longer when an emergency operation was performed immediately before admission to the ICU (p < 0.0001). However, although patients requiring emergency operations may be in poorer condition, it is impossible to be sure of the facts, since APACHE scores were not calculated in this study and hence no comparison can be made among patients with illnesses of different severity. The final multiple logistic regression model dealing with the relationship between the 28-day mortality rate and other correlated covariates showed that the longer the INR of the patient, the higher the chance of death within 28 days (p = 0.029). This relationship strongly suggests that the INR should be controlled within a normal range in order to lower the 28-day rate but, according to the international guidelines (Dellinger et al., 2013a), no studies suggest the use of fresh frozen plasma to correct laboratory clotting
abnormalities for patients who are not bleeding. We may need further research to clarify the relationship between prolonged INR and 28-day mortality.
Limitations of the study As mentioned in the discussion section above, the sample size and the estimation of ICU mortality were limited by the methods we used to recruit subjects. Recruitment was simply by way of the ICU admission diagnosis, and then a case record review to exclude those either not fitting the inclusion criteria or fulfilling the exclusion criteria, while many other studies have used different methods to recruit their subjects, such as searching the hospital electronic records of discharge diagnoses. Patients diagnosed with severe sepsis or septic shock after their admission to ICU will therefore be missed in this study, which may be one reason for such a low ICU mortality rate when compared with other studies. Hence, the low rate may not reflect the true situation and further research into the issue is clearly required. Additionally, the amount of crystalloid and norepinephrine administered per kilogram per minute was limited by the lack of any body weight measurement in the ICU, and hence restricts any comparison between local and international studies, and all international guidelines. Another limitation is the severity of the patient’s condition. The type of patients in the study may have been in poorer condition and hence required ICU admission. This may have affected the total volume and amount of crystalloids and norepinephrine infusion plus the duration of mechanical ventilation. However, it is not possible to know for certain, since APACHE scores were not calculated in this study, and so a comparison of its results with those of other local or international studies is not possible as far as the severity of the patients’ condition is concerned.
Conclusion In summary, we hope this study may provide local and international healthcare workers with more information about the clinical management of ICU patients in Hong Kong suffering from severe sepsis or septic shock, and about their subsequent clinical outcomes. What this study adds to the present body of knowledge about such patients includes: (1) the mean duration of norepinephrine infusion in ICU for septic shock patients is almost three days; (2) the more crystalloid is required to correct the hypoperfusion, the higher dosage and longer duration of norepinephrine infusion will be required; (3) the longer the patient’s INR, the higher the chance of death within 28 days. Since no patients had their body weight measured on or after admission to the ICU, we suggest further research on any indirect estimation of body weight by other means, such as anthropometrics measures, to guide the use of drugs and nutritional support in the ICU. In addition, APACHE scores should be calculated in any further study, in order to compare the severity of the patients’ condition with that in other studies. Furthermore, since this study does not cover any university hospital ICU, we suggest that further research on such patients should compare and reflect similarities and differences between public and university hospitals in the territory.
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005
+Model YICCN-2386; No. of Pages 7
ARTICLE IN PRESS
Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock
Funding The authors have no sources of funding to declare.
Conflict of interest The authors have no conflict of interest to declare.
References Beale RJ, Hollenberg SM, Vincent JL, Parrillo JE. Vasopressor and inotropic support in septic shock: an evidence-based review. Crit Care Med 2004;32:S455—65. Bellomo R. Noradrenaline: friend or foe? Heart Lung Circ 2003;12(Suppl. 2):S42—8. Beovic B, Hladnik Z, Pozenel P, Siuka D, Slovenian Severe Sepsis Study G. Epidemiology of severe sepsis in Slovenian intensive care units for adults. J Chemother 2008;20:134—6. Casserly B, Gerlach H, Phillips GS, Lemeshow S, Marshall JC, Osborn TM, et al. Low-dose steroids in adult septic shock: results of the Surviving Sepsis Campaign. Intensive Care Med 2012;38:1946—54. Cheng B, Xie G, Yao S, Wu X, Guo Q, Gu M, et al. Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Crit Care Med 2007;35:2538—46. De Backer D, Aldecoa C, Njimi H, Vincent JL. Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis*. Crit Care Med 2012;40:725—30. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32: 858—73. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 2008;34:17—60. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Intensive Care Med 2013a;39:165—228. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013b;41:580—637. Elias AC, Matsuo T, Grion CM, Cardoso LT, Verri PH. Incidence and risk factors for sepsis in surgical patients: a cohort study. J Crit Care 2012;27:159—66. Ferguson-Myrthil N. Vasopressor use in adult patients. Cardiol Rev 2012;20:153—8. Gray A, Ward K, Lees F, Dewar C, Dickie S, McGuffie C, et al. The epidemiology of adults with severe sepsis and septic shock in Scottish emergency departments. Emerg Med J 2013;30:397—401. Hernandez G, Bruhn A, Romero C, Larrondo FJ, De La Fuente R, Cornejo R, et al. Implementation of a norepinephrine-based
7
protocol for management of septic shock: a pilot feasibility study. J Trauma 2006;60:77—81. Hodgin KE, Moss M. The epidemiology of sepsis. Curr Pharm Des 2008;14:1833—9. Jaramillo-Bustamante JC, Marin-Agudelo A, Fernandez-Laverde M, Bareno-Silva J. Epidemiology of sepsis in pediatric intensive care units: First Colombian Multicenter Study. Pediatr Crit Care Med 2012;13(5):501—8. Khan MR, Maheshwari PK, Masood K, Qamar FN, Haque AU. Epidemiology and outcome of sepsis in a tertiary care PICU of Pakistan. Indian J Pediatr 2012;79(11):1454—8. Lamontagne F, Cook DJ, Adhikari NK, Briel M, Duffett M, Kho ME, et al. Vasopressor administration and sepsis: a survey of Canadian intensivists. J Crit Care 2011;26:532 e1—e5327. Merouani M, Guignard B, Vincent F, Borron SW, Karoubi P, Fosse JP, et al. Norepinephrine weaning in septic shock patients by closed loop control based on fuzzy logic. Crit Care 2008;12:R155. Miller RR 3rd, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst DR, et al. Multicenter implementation of a severe sepsis and septic shock treatment bundle. Am J Respir Crit Care Med 2013;188:77—82. Moore LJ, McKinley BA, Turner KL, Todd SR, Sucher JF, Valdivia A, et al. The epidemiology of sepsis in general surgery patients. J Trauma 2011;70:672—80. Neviere R. Pathophysiology of sepsis; 2013a. Neviere R. Sepsis and the systematic inflammatory response syndrome: definitions, epidemiology, and prognosis; 2013b. Phua J, Koh Y, Du B, Tang Y-Q, Divatia JV, Tan CC, et al. Management of severe sepsis in patients admitted to Asian intensive care units: prospective cohort study. Brit Med J 2011;342:d3245. Pociello Alminana N, Balaguer Gargallo M, Jordan Garcia I, Corrales Magin E, Esteban Torne E, Munoz Almagro C, et al. Epidemiology and clinical findings in late-onset neonatal sepsis in the pediatric intensive care unit. An Pediatr (Barc) 2007;67:604—5. Sandifer JP, Jones AE. Dopamine versus norepinephrine for the treatment of septic shock EBEM commentators. Ann Emerg Med 2012;60(3):372—3. Suka M, Yoshida K, Takezawa J. Incidence and outcome of sepsis in Japanese intensive care units: the Japanese nosocomial infection surveillance system. Environ Health Prev Med 2006;11:298—303. Tsapenko MV, Herasevich V, Mour GK, Tsapenko AV, Comfere TB, Mankad SV, et al. Severe sepsis and septic shock in patients with pre-existing non-cardiac pulmonary hypertension: contemporary management and outcomes. Crit Care Resusc 2013;15:103—9. Vasu TS, Cavallazzi R, Hirani A, Kaplan G, Leiby B, Marik PE. Norepinephrine or dopamine for septic shock: systematic review of randomized clinical trials. J Intensive Care Med 2012;27:172—8. Vincent JL, Atalan HK. Epidemiology of severe sepsis in the intensive care unit. Br J Hosp Med (Lond) 2008;69:442—3. Wang M, Peng W, Cai M, Ji G. Investigation on epidemiology in 645 cases with sepsis in surgical intensive care unit. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2006;18:74—7. Whittaker SA, Mikkelsen ME, Gaieski DF, Koshy S, Kean C, Fuchs BD. Severe sepsis cohorts derived from claims-based strategies appear to be biased toward a more severely ill patient population. Crit Care Med 2013;41:945—53.
Please cite this article in press as: Cheung WK, et al. Clinical management for patients admitted to a critical care unit with severe sepsis or septic shock. Intensive Crit Care Nurs (2015), http://dx.doi.org/10.1016/j.iccn.2015.04.005