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Department of Clinical Surgery, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK. Tel: +44 131 242 3631. Fax: +44 131 242 3617.
A liver resection under low central venous pressure (CVP) has become standard practice; however, the benefits beyond a reduction in blood loss are not well reported. Moreover, the precise method to achieve CVP reduction has not been established. A systematic review and meta analysis of randomized controlled trials (RTCs) was performed to assess the effects of CVP on clinical outcome and to identify the optimum method of CVP reduction.
Methods
EMBASE, Medline, PubMed and the Cochrane database were searched for trials comparing low CVP surgery with controls. The primary outcome was post operative complications within 30 days. Secondary outcomes included estimated blood loss (EBL), blood transfusion rates and length of stay (LOS). Sub group analysis was performed to assess the CVP reduction method on the outcome.
Results
Eight trials were identified. No difference was observed in the morbidity rate between the high CVP and control groups [odds ratio (OR) = 0.96 (95% confidence interval (CI) 0.66, 1.40) P = 0.84, I2 = 0%]. EBL [weighted mean difference (WMD) = −308.63 ml (95% CI −474.67, −142.58) P = < 0.001, I2 = 73%] and blood transfusion rates [OR 0.65 (95% CI 0.44, 0.97) P = 0.040, I2 = 37%] were significantly lower in the low CVP groups. Neither anaesthetic nor surgical methods of CVP reduction were associated with a reduced post operative morbidity.
Conclusion
Low CVP surgery is associated with a reduction in EBL; however, this does not translate into an improvement in post operative morbidity. The optimum method of CVP reduction has not been identified.
Introduction
Liver resectional surgery is frequently the only opportunity for curative treatment of a number of primary and secondary tumours. While it is complex surgery, mortality rates in high volume centres should be < 5%.
Enhanced Recovery After Surgery (ERAS) protocols after a liver resection have increased in popularity in recent years and several studies have highlighted not only the feasibility and safety of fast track protocols
Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: analysis of 1222 consecutive patients from a prospective database.
Methods to reduce intra operative blood loss have included techniques to reduce the central venous pressure (CVP) during a liver resection. The maintenance of a low CVP is currently routine practice during liver surgery.
Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: analysis of 1222 consecutive patients from a prospective database.
Moreover, new techniques have been introduced to reduce CVP, the efficacy of which is not well established. This review aims to assess techniques for CVP reduction on clinical outcomes after a liver resection.
Methods
This study was conducted according to the PRISMA guidelines for meta analysis conduct.
The protocol was registered prospectively on the PROSPERO database for meta analyses (registration number CRD42014007651).
A literature search was performed independently by two researchers of EMBASE, Medline, PubMed and the Cochrane databases. The databases were searched from 1966 to 2014 with the following terms: ‘central venous pressure’ or ’CVP‘ and ’liver resection‘ or ’liver surgery‘ or ’hepatic resection‘ or ’hpb’.
All abstracts were reviewed for relevance by two independent investigators. Relevant full text articles were subsequently reviewed and critiqued.
Inclusion criteria
The inclusion criteria were randomized controlled trials (RCTs) that compared significantly different CVPs or compared a low CVP group with a control group and reported on patient outcomes (morbidity, EBL and LOS) after an elective open liver resection.
Exclusion criteria
Non randomized trials were excluded. Trials that did not report significantly different CVPs between groups did not compare a low CVP with a control group or did not report outcomes of EBL and/or morbidity rate were excluded. All reviews were excluded. Irrelevant studies, letters, case reviews, paediatric populations and animal studies were excluded. Non hepatic surgery and trials including transplant recipients were excluded.
Intervention
The intervention investigated was a reduction in intra operative CVP. This was defined as a statistically significant difference in CVP between groups, or a 'low CVP‘ group compared with a control group. Where multiple recordings of CVP were reported, the CVP during a liver parenchymal transection was used.
Comparator
The comparator group was the study arm where a significantly higher intra operative CVP was reported or the 'control‘ group. The comparator group was defined as demonstrating a higher CVP (mmHg), regardless of absolute CVP value or technique used to achieve CVP.
Outcomes
Primary outcome
The primary outcome was a composite end point of the occurrence of one or more systemic complication within 30 days of a liver resection. Specific blood test abnormalities were not regarded as systemic complications.
Secondary outcome
Further comparisons were made between low CVP groups and control groups. The mean CVP (mmHg/cm H20) during the operation (during transection if multiple readings were provided) was compared between groups. EBL in millilitres and LOS (recorded in whole days) were also compared between groups. CVP lowering protocols were also recorded and compared.
Subgroup analysis
Subgroup analysis was performed according to technique of CVP reduction: anaesthetic methods [intravenous infusion (IVI) restriction, epidural, vasodilators and/or diuretics] and surgical methods (IVC clamping/total or selective vascular hepatic exclusion).
Data extraction
Abstracts were reviewed for relevance and suitability for inclusion by two independent investigators. Full text articles were reviewed, and data were extracted using pre designed data extraction forms. If data were not presented in a format conducive to data synthesis, the authors were contacted using the published correspondence details. In the event of no response, an attempt to contact authors was made by repeat email, followed by a letter and/or phone call. Where no author response was received, the medians and ranges were converted to mean/standard deviation using methods described by Hozo et al.
Statistical analysis was performed using review manager (RevMan ver 5.2; The Nordic Cochrane Centre, Copenhagen, Denmark). The following outcomes were treated as dichotomous data and were analysed using pooled odds ratios (ORs): primary outcome major complication rate, intra operative blood transfusion requirement. The following outcomes were treated as continuous data and were analysed with a weighted mean difference (WMD): EBL, LOS. Statistical significance was set at P < 0.05. Heterogeneity was assessed using I2 and X2 and adjudged to be significant if I2 >50% and/or P < 0.05.
Results
Included trials
The PRISMA diagram of included trials is shown in Fig. 1. Eight randomized controlled trials (RCTs) met the inclusion criteria with 339 patients with a significantly lower CVP and 342 control patients.
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
Patient demographics and indications for a hepatic resection are displayed in Table 1. Bias assessment scores for included trials are presented in Table 2.
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
maintained a low CVP in both groups and observed the effect of milrinone on the operative field without reporting EBL or the complication rate; Sand et al.
incorporated five randomized groups and assessed EBL as volume per transection area and did not report morbidity or LOS. It was felt that this was not meaningfully comparable to the other included studies and so excluded from the quantitative analysis.
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
the CVP was significantly reduced in the low CVP group (n = 291) compared with the control groups (n = 294) [WMD −2.37 mmHg (95% CI −4.11, −0.63) P = 0.008, I2 = 92%]. No difference in in flow occlusion time was observed in the low CVP group (n = 223) compared with the control group (n = 227) in the trials that reported using it [WMD 0.21 min (95%CI −1.47, 1.88) P = 0.810, I2 = 23%].
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
performed an RCT comparing complete in flow occlusion with selective in flow occlusion and observed a significant difference in CVP between the two groups
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
with a total of 490 patients (low CVP n = 243, control n = 247) reported overall systemic complication rates between the groups. There was no difference in the overall morbidity rate between low and high CVP surgery [OR=0.96 (95% CI 0.66,1.40) P = 0.840, I2 = 0%, Fig. 2].
Subgroup analysis was performed according to the method of CVP reduction (i.e. anaesthetic or surgical). The two trials that used anaesthetic techniques to reduce CVP
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
not included in the quantitative analysis did not report any significant differences in post operative renal functioning between the two groups. Sub group analysis of the two trials comparing IVC clamping (n = 161) versus no IVC clamping (n = 159)
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
comprising 553 patients (low CVP n = 276, control n = 277) reported EBL. There was a significant reduction in EBL in the low CVP group compared with the control group [WMD = −308.63 ml (95% CI −474.67, −142.58) P < 0.001, I2 = 73%]. Subgroup analysis
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
demonstrated that anaesthetic measures to reduce CVP (n = 98) led to a significantly reduced EBL compared with the control (n = 98) (WMD = −406.26 ml, CI −499.77, −321.76, P = <0.001, I2 = 52). Sub group analysis of two trials comparing IVC clamping (n = 139) with no IVC clamping (n = 138)
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
including 681 patients (low CVP n = 339, control n = 342). Significantly fewer blood transfusions were required in patients in the low CVP group compared with the control group [OR 0.65 (95%CI 0.44, 0.97) P = 0.040, I2 = 37%].
with 407 patients (low CVP n = 203, control n = 204). No significant difference was observed between the low CVP group and the control group [WMD −1.75 days (95% CI −5.84, 2.34), P = 0.400 I2 = 64%].
Discussion
This review demonstrates that low CVP surgery reduces EBL and blood transfusion rates after a liver resection. However, this does not correspond to improved outcomes in terms of morbidity or hospital stay.
Two other reviews have assessed the effect of CVP reduction on EBL.
meta analysed three and five studies, respectively, comparing low CVP with high CVP and found a significant reduction in blood loss during the low CVP surgery. This present review includes a further three RCTs assessing high and low CVP,
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
discriminates between the anaesthetic and surgical methodology and investigates quantitatively the effect of CVP reduction not only on EBL but also morbidity. This review further demonstrates the beneficial effects of a lower CVP during a transection when compared with higher CVPs in terms of intra operative blood loss and blood transfusion rates. This consolidates the data from the previous reviews.
As well as the previous reviews of RCTs, retrospective series exist which have shown low CVP to be safe and associated with satisfactory EBL and outcomes
Perioperative outcomes of major hepatic resections under low central venous pressure anesthesia: blood loss, blood transfusion, and the risk of postoperative renal dysfunction.
retrospectively concluded that those patients undergoing a resection with CVP >5 mmHg suffered a higher EBL. These published series have often guided practice, and low CVP surgery is regarded as a standard practice.
Controversy remains regarding the evidence base for this issue with several trials
performed a sub group analysis of CVP greater and less than 5 mmHg from their cohort (all using the same protocol) and did not observe a difference in blood loss in living donor patients.
Moreover, two of the included trials in the current analysis
showed a mean reduction by only 150 ml despite all achieving significant reductions in CVP. The reason for the modest reduction in EBL seen in these three included trials is potentially explained by the methodology. The overall difference in CVP between these groups was low and despite statistical significance in difference observed, a clinically significant difference is less obvious. Zhu et al.
had a control group as a low CVP group achieved by standard techniques compared with the IVC clamping group. Therefore, the comparisons in the meta analysis were not all uncontrolled high CVP versus low CVP (although the difference between mean CVPs in these groups was statistically significant). When CVP difference was larger, a more significant difference in EBL was observed.
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
This finding is suggestive of the importance of well controlled CVP and does not identify benefits associated with ultra low CVP.
It is well established that a high blood loss and blood transfusion intra operatively has a negative effect on peri operative complication rates and a reduction in EBL leads to improved post operative outcomes.
Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: analysis of 1222 consecutive patients from a prospective database.
that could have potentially influenced the analysis. The reported difference in EBL in these trials was around 100–200 ml less than the control group. This is much less than compared with the other included trials.
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
Intuitively it can be appreciated why a large drop in EBL could contribute to an improved outcome, and a modest reduction would not necessarily translate into an enhanced post operative course.
However, it is also important to consider the methodology of the techniques used to reduce CVP and their impact on the outcome. Three of the trials compared IVC clamping to reduce CVP compared with no IVC clamping. The potential hazards of IVC clamping have not fully been investigated. A negative effect on hepatic and renal function has not been routinely observed;
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
were reported. Such complications could negate the benefit of low CVP and low blood loss surgery. Considering the lack of benefit gained by this technique in terms of EBL and outcome when compared with standard practice, the routine performance of IVC clamping during transection cannot be supported.
A potential explanation for the negative result in morbidity rates from the anaesthetic studies is the small numbers of participants in the included RCTs. Only two of the anaesthetic trials reported systemic complication rates. These both showed improved outcomes (although not statistically significant) in the low CVP group. These trials are likely to have been under powered to detect a difference in systemic complications. The subgroup analysis in the present meta analysis also failed to detect a significant difference in systemic complications, and a type II error may be present. However, the two trials included in the meta analysis
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
did not report significant differences in renal or hepatic function despite significant reductions in EBL. Therefore, a clinical benefit to low CVP surgery is not unequivocally presented by the evidence.
Another explanation for similar morbidity rates between the groups is the potentially detrimental impact of the individual techniques used to reduce CVP by anaesthetic methods.
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
Intravenous (IV) fluid restriction during the transection phase, glycerine trinitrate (GTN) and furosemide were frequently utilized by the included studies. These simple methods help to maintain a state of hypovolaemia and vasodilation reduces hepatic vein backpressure, which in turn reduces venous bleeding during hepatic transection. The potential for renal dysfunction has not been established.
Perioperative outcomes of major hepatic resections under low central venous pressure anesthesia: blood loss, blood transfusion, and the risk of postoperative renal dysfunction.
have performed assessments of single anaesthetic techniques in low CVP surgery. These studies did not fulfil the criteria for inclusion into the meta analysis. Sand et al.
investigated the benefit of positional change with or without PEEP on CVP during liver resection, finding a head up tilt to be successful in reducing CVP. Several studies in this review performed a positional change to reduce CVP.
found that the CVP rose in the head down position but fell in the head up position. Given that the hepatic vein pressure did not change regardless of position, and that head up tilt is associated with gas embolism and haemodynamic instability,
assessed the effect of milrinone on CVP and the operative field. Milirone was suggested as beneficial owing to its inotropic as well as vasodilatory effect that would prevent the haemodynamic instability of fluid restriction or vasodilation with nitrates. The results were favourable although the study only assessed living donors, and so its effect on patients with significant co morbidities is not yet established.
Another technique that was utilized sparingly by the included trials was an epidural blockade. In a study by Rahbari et al.,
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
epidural anaesthesia used in the control group was associated with a significantly reduced CVP compared with IVC clamping. There is a lack of consensus among non randomized trials with two trials not demonstrating an effect on blood loss when using an epidural in the CVP lowering protocol
This is a particularly pertinent issue relating to a liver resection as the opinion regarding routine epidural use remains divided. The advocates of an epidural would welcome its inclusion peri operatively owing to the perceived improvement in post operative pain, the attenuation of the inflammatory response and a reduction in morbidity rates.
Such disadvantages are often accepted owing to perceptions of improved overall outcomes. However, this concept has been increasingly challenged as alternatives to epidurals are becoming more widespread, and enhanced recovery protocols improve the speed of recovery often without the need for an epidural.
Fast track liver resection: the effect of a comprehensive care package and analgesia with single dose intrathecal morphine with gabapentin or continuous epidural analgesia.
combined IVC clamping within flow occlusion. This could potentially result in a deleterious effect on outcome owing to a potential ischaemia associated liver injury.
A prospective randomized controlled trial to compare Pringle maneuver, hemihepatic vascular inflow occlusion, and main portal vein inflow occlusion in partial hepatectomy.
A prospective randomized controlled trial to compare pringle manoeuvre with hemi hepatic vascular inflow occlusion in liver resection for hepatocellular carcinoma with cirrhosis.
whereby selective inflow occlusion rather than complete in flow occlusion was associated with a significantly reduced post operative morbidity. All maintained a CVP of less than 5 mmHg, there was no difference in blood loss, but Ni et al.
A prospective randomized controlled trial to compare pringle manoeuvre with hemi hepatic vascular inflow occlusion in liver resection for hepatocellular carcinoma with cirrhosis.
A prospective randomized controlled trial to compare Pringle maneuver, hemihepatic vascular inflow occlusion, and main portal vein inflow occlusion in partial hepatectomy.
reported a reduction in morbidity in the selective Pringle groups when compared with the Pringle groups. This, therefore, points to other areas of protocol optimization to consider when CVP has been optimized below 5 mmHg.
Whie the results of the present meta analysis did not demonstrate a significant reduction in morbidity in the low CVP group, other advantages of low CVP surgery merit discussion. A reduction in bleeding during transection has practical implications that warrant consideration. Patient preference to avoid a blood transfusion is important. Furthermore, surgeons' assessment of the operative field and ease of surgery are important factors when attempting to improve short and long term outcomes. Such qualitative metrics was not assessed in the included trials, and these outcomes may be the subject of future research.
The main limitation of this review is the heterogeneity of the included studies. The anaesthetic studies assessed a CVP of over five with a CVP of <5 mmHg. The IVC clamping studies, despite significant differences in CVP, assessed a CVP of <5 mmHg in both groups. It is, therefore, unsurprising that little difference is seen in the outcome. However, the primary aim of all the included trials was to assess the effect of CVP lowering. Therefore, the included trials provide an accurate reflection of current practice in hepatic surgery.
In summary, this review and meta analysis shows that low CVP surgery effectively results in reduced blood loss and transfusion requirement during a liver resection and its practice is supported. However, no improvement in clinical outcomes is associated with this, and this may be affected by methodology. IVC clamping does not improve outcome over low CVP surgery achieved by standard CVP lowering techniques and is not advised. The optimum technique to achieve a CVP reduction is not known with controversies existing regarding the correct anaesthetic technique and potential disadvantages of using the Pringle manoeuvre. Prospective, randomized trials are required to establish precise protocol components when attempting to optimize outcomes after a liver resection.
Conflicts of interest
None to declare.
Acknowledgements
No funding was obtained for this study. This article is being submitted as a review and has not been presented elsewhere.
References
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Trends in perioperative outcome after hepatic resection: analysis of 1500 consecutive unselected cases over 20 years.
Improving perioperative outcome expands the role of hepatectomy in management of benign and malignant hepatobiliary diseases: analysis of 1222 consecutive patients from a prospective database.
(Available at)Higgins J.P.T. Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated arch 2011]. The Cochrane Collaboration. 2011(last accessed 1 May 2014)
The role of adoption of low central venous pressure in hepatic resection with pringle manoeuvre in reducing blood loss and improving operative outcome.
Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial.
Perioperative outcomes of major hepatic resections under low central venous pressure anesthesia: blood loss, blood transfusion, and the risk of postoperative renal dysfunction.
Fast track liver resection: the effect of a comprehensive care package and analgesia with single dose intrathecal morphine with gabapentin or continuous epidural analgesia.
A prospective randomized controlled trial to compare Pringle maneuver, hemihepatic vascular inflow occlusion, and main portal vein inflow occlusion in partial hepatectomy.
A prospective randomized controlled trial to compare pringle manoeuvre with hemi hepatic vascular inflow occlusion in liver resection for hepatocellular carcinoma with cirrhosis.
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